Clinical trial NCT05578872
Conditions: Melanoma (Skin) Cutaneous Melanoma Adult Disease Advanced Solid Tumor Metastatic Melanoma
Keywords: IL-2 ANV419 Cancer Melanoma OMNIA Cutaneous Metastatic Anti-PD1
Sponsor: Anaveon AG
Start date: 2022-12-16; Completion date: 2024-08-01
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of ANV419 monotherapy or the combination of ANV419 with anti-PD1 antibody or with anti-CTLA4 antibody in adult participants with advanced (unresectable or metastatic) cutaneous melanoma. The study has 3 parts. Part 1 to evaluate ANV419 in monotherapy and Parts 2 and 3 to evaluate ANV419 in combination with anti-PD1 antibody or anti-CTLA4 antibody. Parts 2 and 3 were not initiated, as the prespecified efficacy criteria to graduate to Part 2 were not met at the interim analysis of Part 1.

Detailed description:
The purpose of this multi-site, open-label, randomized, parallel arm, Phase 1/2 adaptive study is to evaluate the efficacy and safety of ANV419 as a monotherapy and in combination with anti-PD1 antibody or anti-CTLA4 antibody in patients aged 18 years or older with advanced Cutaneous Melanoma who have previously been treated with an anti-PD-1/anti-PD-L1 antibody.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: ANV419
Intervention descriptions: intervention 1: ANV419 administered by intravenous (IV) infusion

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
OMNIA-1, A Phase 1/2 Study of ANV419 as Monotherapy or in 
Combination With Anti-PD-1 or Anti-CTLA-4 Antibody Following 
Anti-PD-1/Anti-PD-L1 Antibody Treatment in Patients With 
Unresectable or Metastatic Cutaneous Melanoma  
Investigational Product: ANV419 
Protocol Number: ANV419-101 
EudraCT Number: 2021-006711-29 
 
 
 
Sponsor: 
Anaveon AG 
Technologiepark Basel 
Hochbergerstrasse 60C 
4057 Basel 
Switzerland 
Telephone: 
 
 
Version Number: 4.0 
Date: 07 March 2023 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Anaveon AG except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Anaveon AG. You are allowed to 
disclose the contents of this document only to your Institutional Review Board or Independent 
Ethics Committee 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 Anaveon AG and that it may not be further disclosed to third parties. 




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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 Anaveon AG 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 Anaveon AG 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 Anaveon AG, 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 Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE: A Phase 1/2 Study of ANV419 as Monotherapy or in Combination With Anti-PD-1 or 
Anti-CTLA-4 Antibody Following Anti-PD-1/Anti-PD-L1 Antibody Treatment in Patients With 
Unresectable or Metastatic Cutaneous Melanoma 
PROTOCOL NUMBER: ANV419-101 
INVESTIGATIONAL PRODUCT: ANV419 
PHASE: 1/2 
INDICATIONS: ANV419 is being developed for treatment of unresectable or metastatic 
cutaneous melanoma (CM) following at least 1 line of standard of care immunotherapy including 
an anti-programmed death-1 [PD-1] and/or anti-programmed death-ligand 1 [PD-L1] antibody. 
OBJECTIVES AND ENDPOINTS: 
The study objectives and endpoints for Part 1: Monotherapy Dose Expansion, Part 2: Combination 
Dose Finding, and Part 3: Combination Dose Expansion are provided in Table TS1, Table TS2, 
and Table TS3. 
Table TS1. 
Study Objectives and Endpoints for Part 1: Monotherapy Dose Expansion 
Part 1: Monotherapy Dose Expansion – Arms A1 and A2 
Primary Objectives
Primary Endpoints
Evaluate the efficacy of 
ANV419
ORR (CR + PR), as defined by RECIST v1.1 (hereinafter, RECIST).
Secondary Objectives 
Secondary Endpoints 
To characterize the 
tumor response 
according to modified 
RECIST v1.1 criteria 
for immune-based 
therapeutics (iRECIST)
Tumor response in terms of objective response rate (ORR: CR + PR) assessed by 
iRECIST
Expand evaluation of 
efficacy of ANV419
- 
DOR (per RECIST) and iDOR (per iRECIST[0]) measured from first response 
until disease progression; 
- 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD), PFS, iPFS, and 
OS; 
- 
Median TTR; and 
-
Median iTTR.
Evaluate the safety of 
ANV419
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs;  
- 
irAEs; 
- 
AESIs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and physical 
examination.
Explore 
immunogenicity after 
exposure to ANV419
Incidence of immunogenicity as indicated by ADA.


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Table TS1. Study Objectives and Endpoints for Part 1: Monotherapy Dose Expansion 
(Continued) 
Part 1: Monotherapy Dose Expansion – Arms A1 and A2
Exploratory 
Objectives
Exploratory Endpoints
Explore the changes in 
the tumor 
microenvironment 
before and after adding 
ANV419 as 
monotherapy 
Changes in immunological biomarker expression from baseline and post treatment 
tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, CD3, 
CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, IL-6, IL-10); 
and 
-
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.
Analysis of changes in baseline ctDNA and at specified timepoints on therapy and 
after therapy. 
Analysis of single nucleotide polymorphisms, germline DNA for genome-wide 
association studies, analysis of T cell receptor repertoire, epigenetic markers, soluble 
CD25, and soluble PD-1/PD-L1. 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for the response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
AE = adverse event; AESI = adverse event of special interest; CD = cluster of differentiation; CR = complete response; 
ctDNA = circulating tumor deoxyribonucleic acid; DCR = disease control rate; DNA = deoxyribonucleic acid; DOR = duration 
of response; ECG = electrocardiogram; FoxP3 = Forkhead box P3; iCR = immune complete response; iDCR = immune disease 
control rate; iDOR = immune duration of response; IFNγ = interferon gamma; IL = interleukin; iPFS = immune 
progression-free survival; iPR = immune partial response; irAE = immune-related adverse event; iRECIST = immune Response 
Evaluation Criteria in Solid Tumors; iSD = immune stable disease; iTTR = immune time to response; ORR = objective 
response 
rate; 
OS 
= 
overall 
survival; 
PD-1 = programmed 
death-1; 
PD-L1 = programmed 
death-ligand 
1; 
PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SD = stable disease; T cell = thymus lymphocyte cell; TNF = tumor necrosis factor; TTR = time 
to response; v1.1 = version 1.1.
 
Table TS2. 
Study Objectives and Endpoints for Part 2: Combination Dose Finding 
Part 2: Combination Dose Finding – Combination Therapy Arms (Arms B and C) 
Primary Objectives 
Primary Endpoints 
Evaluate the safety and 
tolerability and 
determine the RP2D of 
ANV419 in combination 
with pembrolizumab
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs; 
- 
TEAEs; 
- 
DLTs; 
- 
AESIs; 
- 
irAEs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and physical 
examinations.
Evaluate the safety and 
tolerability and 
determine the RP2D of 
ANV419 in combination 
with ipilimumab
Secondary Objectives 
Secondary Endpoints 
Evaluate PK and PD of 
ANV419 in combination 
with pembrolizumab or 
ipilimumab
PK endpoints in serum: 
- 
CL of ANV419; 
- 
Vss of ANV419; 
- 
AUC of ANV419; and 
- 
Cmax of ANV419. 
 
PD endpoints in peripheral blood: including, but not limited to, CD3, CD4, CD8, 
CD56, CD16, CD25, FoxP3, CD279, and CD366.


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Table TS2. Study Objectives and Endpoints for Part 2: Combination Dose Finding 
(Continued) 
Part 2: Combination Dose Finding – Combination Therapy Arms (Arms B and C) 
Secondary Objectives 
Secondary Endpoints 
Explore immunogenicity 
after exposure to 
ANV419 in combination 
with pembrolizumab or 
ipilimumab
Incidence of immunogenicity as indicated by ADA.
Evaluate the efficacy of 
ANV419 in combination 
with pembrolizumab or 
ipilimumab
ORR (CR + PR), as defined by RECIST.
Expand evaluation of 
efficacy of ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
DOR (per RECIST) and iDOR (per iRECIST[1]) measured from first response until 
disease progression; 
PFS, iPFS, and OS; 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD),  
Median TTR; and 
Median iTTR.
Evaluate clinical benefit 
in quality of life after 
exposure to ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
Change in QoL at baseline and every 12 weeks while receiving ANV419 via QoL 
evaluations:  
- 
EQ-5D-5L; and 
-
QLQ-C30.
Exploratory Objectives
Exploratory Endpoints
Explore the changes in 
the tumor 
microenvironment 
before and after adding 
ANV419 as 
monotherapy and in 
combination with 
pembrolizumab or 
ipilimumab
Changes in immunological biomarker expression from baseline and post treatment 
tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, CD3, 
CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, IL-6, 
IL-10); and 
-
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.
Analysis of changes in baseline ctDNA and at specified timepoints on therapy and 
after therapy.
Analysis of single nucleotide polymorphisms, germline DNA for genome-wide 
association studies, analysis of T cell receptor repertoire, epigenetic markers, soluble 
CD25, and soluble PD-1/PD-L1.
ADA = anti-drug antibodies; AE = adverse event; AESI = adverse event of special interest; AUC = area under the 
concentration-time curve; CD = cluster of differentiation; CL = systemic clearance; Cmax = maximum observed serum 
concentration; CR = complete response; ctDNA = circulating tumor deoxyribonucleic acid; DLT = dose-limiting toxicity; 
ECG = electrocardiogram; EQ-5D-5L = Euro-QoL 5 dimension 5 level; FoxP3 = Forkhead box P3; IFNγ = interferon gamma; 
IL = interleukin; irAE = immune-related adverse event; ORR = objective response rate; PD = pharmacodynamic(s); 
PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; PK = pharmacokinetic(s); PR = partial response; 
QLQ-C30 = quality of life core 30; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; 
RP2D = recommended 
Phase 
2 
dose; 
SAE = serious 
adverse 
event; 
T 
cell = thymus 
lymphocyte 
cell; 
TEAE = treatment-emergent adverse event; TNF = tumor necrosis factor; Vss = volume of distribution at steady state.
 
 
 
 


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Table TS3. 
Study Objectives and Endpoints for Part 3: Combination Dose Expansion 
Part 3: Combination Dose Expansion – Combination Therapy Arms (Arms B and C) 
Primary Objectives
Primary Endpoints
Evaluate the efficacy of 
ANV419 in 
combination with 
pembrolizumab or 
ipilimumab 
ORR (CR + PR), as defined by RECIST.
Table TS3. Study Objectives and Endpoints for Part 3: Combination Dose Expansion 
(Continued) 
Part 3: Combination Dose Expansion – Combination Therapy Arms (Arms B and C) 
Secondary Objectives 
Secondary Endpoints 
Expand evaluation of 
efficacy of ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
- 
DOR (per RECIST) and iDOR (per iRECIST[1]) measured from first response 
until disease progression; 
- 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD), PFS, iPFS, and 
OS; 
- 
Median TTR; and 
-
Median iTTR.
Evaluate the safety of 
ANV419 in 
combination with 
pembrolizumab or 
ipilimumab 
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs;  
- 
irAEs; 
- 
AESIs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and physical 
examination.
Evaluate clinical 
benefit in quality of life 
after exposure to 
ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
Change in QoL at baseline and every 12 weeks while receiving ANV419 via QoL 
evaluations:  
- 
EQ-5D-5L; and 
-
QLQ-C30.
Explore 
immunogenicity after 
exposure to ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
Incidence of immunogenicity as indicated by ADA.
Exploratory 
Objectives
Exploratory Endpoints
Explore the changes in 
the tumor 
microenvironment 
before and after adding 
ANV419 in 
combination with 
pembrolizumab or 
ipilimumab
Changes in immunological biomarker expression from baseline and post treatment 
tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, CD3, 
CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, IL-6, IL-10); 
and 
-
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.
Analysis of changes in baseline ctDNA and at specified timepoints on therapy and 
after therapy.
Analysis of single nucleotide polymorphisms, germline DNA for genome-wide 
association studies, analysis of T cell receptor repertoire, epigenetic markers, soluble 
CD25, and soluble PD-1/PD-L1.


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1. 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for the response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
AE = adverse event; AESI = adverse event of special interest; CD = cluster of differentiation; CR = complete response; ctDNA = 
circulating tumor deoxyribonucleic acid; DCR = disease control rate; DOR = duration of response; ECG = electrocardiogram; EQ-5D-
5L = Euro-QoL 5 dimension 5 level; FoxP3 = Forkhead box P3; iCR = immune complete response; iDCR = immune disease control 
rate; iDOR = immune duration of response; IFNγ = interferon gamma; IL = interleukin; iPFS = immune progression-free survival; iPR 
= immune partial response; irAE = immune-related adverse event; iRECIST = immune Response Evaluation Criteria in Solid Tumors; 
iSD = immune stable disease; iTTR = immune time to response; ORR = objective response rate; OS = overall survival; 
PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PR = partial response; 
QLQ-C30 = quality of life core 30; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious 
adverse event; SD = stable disease; T cell = thymus lymphocyte cell; TNF = tumor necrosis factor; TTR = time to response.


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POPULATION: 
Patients with unresectable or metastatic cutaneus melanoma with measurable disease, whose 
disease has progressed following at least 1 line of standard of care immunotherapy including an
anti-PD-1/ anti-PD-L1 antibody. 
Inclusion criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Must provide written informed consent for the study; 
2. Must be able to comply with the Protocol as judged by the Investigator; 
3. Are 18 years of age on day of signing informed consent; 
4. Have histologically confirmed Stage 3 (unresectable) or Stage 4 (metastatic) CM, as per the 
American Joint Committee on Cancer staging system, eighth edition;  
5. Have documented radiological progression on prior systemic therapy; 
6. Have previously received anti-PD-1/L1 as monotherapy or in combination. A maximum of 2 
prior lines of systemic therapy is allowed for BRAF wild-type disease and a maximum of 3 
prior lines of systemic therapy is allowed for BRAFV600 positive disease; 
Note: Adjuvant treatment is considered as a line of therapy only if patient experienced relapse/ 
progression on therapy or within 6 months from adjuvant therapy completion; 
7. Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1 (hereinafter, RECIST); 
8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Status; 
9. Have adequate organ functions as defined in Table TS4: 
 
Table TS4. 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological
ANC
1500/µL
Platelets
100,000/µL
Hemoglobin
9 g/dL or 4.96 mmol/L
Renal
Measured or calculated[1] CrCl 
(GFR can also be used in place 
of CrCl)
30 mL/min 
Hepatic
Serum total bilirubin OR direct 
bilirubin
1.5 × ULN OR 1.5 × ULN for patients with total bilirubin levels 
1.5 × ULN; direct bilirubin 1.5 × ULN for patients with Gilbert’s 
syndrome
AST (SGOT) or ALT (SGPT)
2.5 × ULN OR 5 × ULN for patients with liver metastases
Albumin
2.5 g/dL
 


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Table TS4. 
Adequate Organ Function Laboratory Values (Continued) 
1. 
CrCl should be calculated per Cockcroft-Gault equation. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine 
clearance; GFR = glomerular filtration rate; SGOT = serum glutamic oxalacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; ULN = upper limit of normal.
10. Female patients of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative (urine or serum) pregnancy test within 72 hours prior to study 
Day 1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required and must be negative for the patient to be eligible; 
11. Female patients who are not postmenopausal, and who have not undergone surgical 
sterilization, must agree to use highly effective methods of contraception during the treatment 
period and for 6 months after the last dose of study drug. They must also agree not to donate 
eggs (ova, oocytes) during the same timeframe; and 
12. Male patients with partners of childbearing potential must agree to use highly effective 
methods of contraception and barrier contraception (condom) during the treatment period and 
for 6 months after the last dose of study drug. They must also agree not to donate sperm during 
the same timeframe. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Have received investigational agent (including investigational device) within 4 weeks or an 
interval of 5 half-lives of the respective investigational agent prior to study Day 1, whichever 
is longer, with the exclusion of an anti-PD-1/anti-PD-L1 antibody given as either a single agent 
or non-CTLA-4 antibody containing combination (eg, anti-lymphocyte-activation gene 3 
antibody); 
2. Have a known hypersensitivity to ANV419 or to any of the excipients, such as sucrose, 
histidine or polysorbate 80. For combination arms only: Have hypersensitivity to 
pembrolizumab or ipilimumab or any of their excipients;  
3. For combination arms only: Have previously discontinued ipilimumab, pembrolizumab, or 
any other PD-1/PD-L1 inhibitors due to unacceptable drug-related toxicity (defined as 
toxicities that required second line immunosuppression, ie, not controlled by steroids alone);
4. Have a lactate dehydrogenase level of 2 × upper limit of normal; 
5. Have not recovered (ie, Grade 1 or at baseline with the exception of alopecia or fatigue 
[up to Grade 2 allowed]) from adverse events (AEs) resulting from prior immunotherapies. 
Patients who have autoimmune AEs controlled by replacement therapy (ie, hypothyroidism) 
due to previous treatment are eligible provided replacement therapy has been initiated and 
toxicity has returned to Grade 1; 
6. Have not recovered (ie, Grade 1 or at baseline) from toxicities due to a previously 
administered chemotherapy, targeted small molecule therapy, or radiation therapy; 
Note: If the patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study drug. Major surgery 
is defined as any surgery requiring entrance into a body cavity (eg, chest, abdomen, or brain), 
organ removal, normal anatomy alteration, or joint replacement. Minor surgery is defined as 


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any surgery in which skin, mucosa, or connective tissue sections are altered (eg, biopsy, 
cataract, endoscopic procedures, etc).  
7. Have been diagnosed with uveal/ocular or mucosal melanoma; 
8. Have a known additional malignancy (including all in-situ carcinoma) that is progressing 
or required active treatment within ≤2 years prior to enrollment. Exceptions include basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin that have undergone potentially 
curative therapy or in situ cervical cancer or patients who completed cancer-directed and have 
no evidence of disease; 
9 Have active central nervous system metastases and/or carcinomatous meningitis. Patients 
with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least 4 weeks prior to study Day 1, and any 
neurologic symptoms have returned to baseline or have been stable for at least 7 days), have 
no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days 
prior to study drug. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability; 
10. Have a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 
7 days prior to study Day 1; 
11. Are receiving systemic steroid 10 mg of prednisone daily or equivalent or any other 
immunosuppressive medication at any dose level. Local steroid therapies (eg, otic, ophthalmic, 
intra-articular, or inhaled medications) are acceptable; 
12. Have an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment;  
13. Have evidence of active, non-infectious pneumonitis; 
14. Have active (measurable) and uncontrolled (unresponsive to current therapy) infectious 
disease (bacterial, fungal, viral, protozoic); 
15. Have a history of an acute coronary event (eg, myocardial infarction) within 3 months prior to 
study Day 1, uncontrolled and symptomatic coronary artery disease or congestive heart failure 
New York Heart Association Class III/IV; 
16. Have an average QTcF interval 470 msec at Screening; 
17. Have a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the full 
duration of the study, or it is not in the best interest of the patient to participate, in the opinion 
of the treating Investigator; 
18. Have known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study;  
19. Are pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the Screening Visit through 6 months after the last dose of 
study drug; 


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20. Are known to be human immunodeficiency virus (HIV) positive (or tests positive for HIV 1
or 2 at Screening), unless the following criteria are met: 
a. Cluster of differentiation (CD)4+ lymphocyte count 350 µL; 
b. Had no history of acquired immunodeficiency syndrome (AIDS)-defining 
opportunistic infections within the past 12 months; 
c. Have been on established anti-retroviral therapy for at least 4 weeks; and 
d. Have an HIV viral load of 400 copies/mL prior to study Day 1. 
Note: Patients on strong cytochrome P450 (CYP)3A4 inhibitors or strong CYP3A4 
inducers must be switched to an alternate effective anti-retroviral therapy regimen prior to 
study treatment or are excluded if regimen prior to study Day 1 cannot be altered. 
21. Have uncontrolled hepatitis B infection or hepatitis C infection; 
Note: Patients with hepatitis B (positive hepatitis B surface antigen) who have controlled 
infection (serum hepatitis B virus DNA by polymerase chain reaction that is below the limit 
of detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with 
controlled infections must undergo periodic monitoring of hepatitis B virus DNA.  
Note: Patients with hepatitis C (positive hepatitis C virus antibody) who have controlled 
infection (undetectable hepatitis C virus RNA by polymerase chain reaction either 
spontaneously or in response to a successful prior course of anti-hepatitis C virus therapy) are 
permitted.  
22. Have received a live vaccine within 30 days of study Day 1; or 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
23. For combination arms only: Have received solid organ or hematopoietic stem cell transplant.
 
STUDY DESIGN AND DURATION: 
This is a multi-site, open label, randomized, parallel arm, Phase 1/2 adaptive study to evaluate the 
efficacy and safety of ANV419 as a monotherapy and in combination with pembrolizumab or 
ipilimumab in patients aged 18 years or older with advanced CM who have previously been treated 
with at least 1 line of standard of care immunotherapy, including an anti-PD-1/ anti-PDL1 
antibody. 
The 4 following treatment arms will be included in this study: 
 Arm A1: ANV419 (
 Q2W); 
 Arm A2: ANV419 (
 µg/kg, Q2W); 
 Arm B: ANV419 (
) in combination with pembrolizumab (Keytruda); and 
 Arm C: ANV419 (
)in combination with ipilimumab (Yervoy). 


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There will be up to 3 separate parts in this study: Part 1: Monotherapy Dose Expansion with 
patients randomized to receive infusion of ANV419 (
 [Arm A1] or 243 µg/kg [Arm A2]
 2 weeks. If Part 1 is successful, Part 2: Combination Dose Finding with patients randomized 
to Arms B and C with infusion of ANV419 
 3 weeks, and finally, Part 3: Combination Dose 
Expansion with patients randomized to Arms B and C (see Figure FS1). A total of up to
130 patients are planned to be enrolled in the study: a maximum of 30 patients in the Monotherapy 
Dose Expansion part, a maximum of 50 patients in the Combination Dose Finding part, and a 
maximum of 50 patients in the Combination Dose Expansion part. Randomization in the 
Monotherapy Dose Expansion part and Combination Dose Expansion part will be stratified by 
BRAF mutation status.  
In the Combination Dose Expansion part, the number of patients within each arm will be 
determined by pre-defined decision rules presented in Table TS6.  
Figure FS1. Study Design 
* = If ANV419 monotherapy is successful, the combination portion will be initiated. 
** = Dose escalation increment is decided by the SRC until RP2D of ANV419 per arm is identified. 
*** = Arm not meeting pre-specified ORR criteria may be stopped early after Stage 1. 
In the Combination Dose Finding part, patients will be manually randomized to Arm B or Arm C. In the Monotherapy Dose 
Expansion part and the Combination Dose Expansion part, patients will be randomized by IRT into Arms A1 or A2 and Arms B 
or C, respectively. 
Ipi = ipilimumab; IRT = Interactive Response Technology; ORR = objective response rate; Pembro = pembrolizumab; R = randomization; 
RP2D = recommended Phase 2 dose; SRC = Safety Review Committee.  
All patients will be assessed for response using RECIST and computed tomography imaging, 
which will occur every  weeks (±7 days) from baseline until Cycle 13 
 the monotherapy arm) 
 every 9 weeks (±7 days) from baseline until Cycle 7 (for combination therapy arms), using the 
same modality as used for baseline imaging until progressive disease per RECIST and immune 
RECIST, withdrawal of consent, or initiation of a new anticancer therapy. Treatment decision will 
be based on local assessment. All images will be collected and stored centrally for potential central 
analysis. 
 Cycle 13 
 the monotherapy arms) or Cycle 7 (for the combination therapy 
 scans should be performed every 12 weeks (±7 days) from the previous assessment. The 
study will also assess other clinical parameters including progression-free survival (PFS) and will 
provide the opportunity to explore blood- and tumor-based markers that may predict response to 
ANV419 as monotherapy or in combination with anti-PD-1 or anti-CTLA-4 antibodies. 
 
 


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Part 1: Monotherapy Dose Expansion 
The Monotherapy Dose Expansion part (Arms A1 and A2) will be a parallel group part with a 
Bayesian sequential monitoring analysisa and up to 15 patients per arm. This part will establish 
the efficacy and safety of ANV419 as monotherapy.  
Initially, two doses of ANV419 will be explored: 
 µg/kg and 243 µg/kg based on data collected 
in the ongoing Phase 1 ANV419-001 study  a frequency of every 2 weeks (Q2W). An additional 
dose of ANV419 may be explored once the final results of ANV419-001 Study will be available. 
Treatment with ANV419 as a monotherapy can continue for up to 
 
 in the absence of disease progression or unacceptable toxicity and in the absence of data 
 an unfavorable risk/benefit profile for patients on ANV419 
.  
Decision making on whether to continue the study beyond the Monotherapy Dose Expansion part, 
and the total number of patients recruited to this part, will be based on Bayesian sequential 
monitoring. The study will be stopped at the end of this part in the case of an unfavorable 
risk/benefit profile for ANV419 monotherapy. This includes observing a total of 0 of 30 responses 
from the 2 monotherapy arms combined (a strong signal that ANV419 does not induce a response) 
and/or report of any safety issues that might stop the trial. There is 95% certainty that the true 
objective response rate (ORR) is greater than 10% if we observe any 1 of the following: 
 2 responses in 3 to 7 patients;  
 3 responses in 8 to 13 patients;  
 4 responses in 14 to 19 patients; or  
 5 responses in 20 to 27 patients. 
Response (complete response [CR] or partial response [PR]) will be assessed at each disease 
evaluation by the Investigator. 
Part 2: Combination Dose Finding 
This part will only be initiated following approval of a substantial amendment supporting the 
ANV419 starting dose in the combination part. The submission will include data from ANV419-
001 Study and from Part 1 of this trial, and occur at any time when at least 2 responses have been 
observed in the Monotherapy Dose Expansion part. The Combination Dose Finding part will be 
comprised of 2 arms (Arms B and C) that will identify a recommended Phase 2 dose (RP2D) for 
ANV419 in each arm when administered in combination with pembrolizumab (Arm B) or 
ipilimumab (Arm C) at the prescribed dosing. The number of patients recruited to each arm will 
be between 6 and 25 patients depending on the number of dose increments possible. A minimum 
of 6 patients will be treated at RP2D. The patients from the Combination Dose Finding part will 
not be randomized into the Combination Dose Expansion part. 
Dosing of ANV419 when administered in combination with pembrolizumab (Arm B) or 
ipilimumab (Arm C) will occur as shown in Table TS5, with a dose of ANV419 currently planned 
to start at 
 µg/kg every 3 weeks (Q3W). Patients in the Combination Dose Finding part will be 
treated with a minimum of 24 hours interval between patients to allow for monitoring of acute 
toxicities. Dose level 1, as shown in Table TS5, will be reviewed by the Safety Review Committee 
 
a. Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. Biometrics. 1994;50(2):337-349. 


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(SRC) per the safety evaluations and the SRC will make dose increment recommendations at each 
dose level, not exceeding 3-fold increment from one dose level to the next. The maximum dose 
level explored will not exceed the Q3W dose of ANV419 monotherapy studied in the ongoing 
ANV419-001 study. The dose-limiting toxicity (DLT) period for the Combination Dose Finding 
part will last for 
 days (1 cycle), beginning at Cycle 1 Day 1 and ending at the end of Cycle 
 21 prior to Cycle 2 Day 1. For details on the DLT criteria for the Combination Dose Finding 
part of this study, see the section below labeled “Dose-limiting toxicity criteria (applicable to 
Combination Dose Finding part only).” 
 
Table TS5.  
ANV419 Dose Escalation Plan for Combination Dose Finding Part 
(Pembrolizumab or Ipilimumab) 
Dose Level 
ANV419 Dose
Pembrolizumab Dose or Ipilimumab Dose
Frequency
1
2
3
4
5
Note: ANV419 will be administered by IV infusion over 15 minutes (+5 minutes).  
Dose increments will be determined by the SRC based on a synthesis of all relevant data available from all dose levels evaluated 
in this study, not exceeding a 3-fold increment from one dose level to the next. The maximum dose level explored will not 
exceed the 
 dose of ANV419 monotherapy studied in the ongoing ANV419-001 study. 
IV = intravenous(ly); 
 = every 3 weeks; SRC = Safety Review Committee; TBD = to be determined.
Dose escalation in the Combination Dose Finding part will follow the Bayesian optimal interval 
(BOIN)a design to find the maximum tolerated doses (MTDs)/RP2D of ANV419 when 
administered in combination with pembrolizumab or ipilimumab at the prescribed dose. Dose 
escalation decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing Combination Dose Finding part of the study. 
Part 3: Combination Dose Expansion 
The Combination Dose Expansion part of the study will be separate from the Combination Dose 
Finding part and will further evaluate the safety and efficacy of ANV419 in combination with 
pembrolizumab (Arm B) or ipilimumab (Arm C). This Combination Dose Expansion part will 
consist of 2 stages. In Stage 1, 12 patients will be randomized by interactive response technology 
(IRT) into each arm. At the end of this stage, an interim analysis will be performed to assess 
continuation of treatment arms into Stage 2 (see Table TS6). In Stage 2, eligible patients will be 
randomized to the remaining treatment arms, determined at the interim analysis. Recruitment will 
continue until 25 patients have been randomized to a treatment arm. 
Table TS6. 
Continuation Decision Rules for Combination Dose Expansion Part 
Treatment Arm 
Accrual
Discontinue if the 
Number of Responses 
is
Discontinue Criterion in Terms of 
ORR 
Continue if the Number 
of Responses is at Least
Stage 1 (n=12)
2
Observed ORR 20%
3
ORR = objective response rate.
Dosing for ANV419 in the combination arms (Arms B and C) in the Combination Dose Expansion 
part will be based on the RP2Ds for ANV419 determined in the Combination Dose Finding part, 
 
a. Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc Ser C Appl Stat. 
2015;64(3):507-523. 


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ie, the RP2D for ANV419 when administered in combination with pembrolizumab (hereinafter, 
RP2D[p]) and the RP2D for ANV419 when administered in combination with ipilimumab 
(hereinafter, RP2D[i]).  
Treatment with ANV419 in combination with pembrolizumab can continue for 24 months within 
the current Protocol in the absence of disease progression or unacceptable toxicity.  
Treatment with ANV419 in combination with ipilimumab can continue up to a maximum of 
4 cycles, per the approved label (United States Prescribing Information and Summary of Product 
Characteristics). If ipilimumab-related AEs occur, ipilimumab can be discontinued at any time. 
Once a patient has completed the maximum of 4 
 of ipilimumab allowed, they will 
 
 ANV419 at the dose enrolled as monotherapy Q3W and may continue for 24 
 
 the current Protocol in the absence of disease progression or unacceptable toxicity.  
Dose-limiting toxicity criteria (applicable to Combination Dose Finding part only) 
A DLT is defined as any of the treatment-emergent AEs (TEAEs) listed below, as defined by the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 5.0, occurring during the DLT period (
 1 Day 1 through Cycle 1 Day 21) and the AE 
is not reasonably attributed to the patient’s underlying disease, other medical conditions, or 
concomitant medications. To be DLT evaluable, the patient must complete 
 1 and 
 
 second dose of the study drug(s). Any patient that discontinues the study before the DLT period 
 over (Cycle 1 Day 1 through Cycle 1 Day 21) or reasons other than DLT or any event that 
renders the patient non evaluable for DLT will be replaced. Patient who experience a delay of 
Cycle 2 dosing longer than 7 days for toxicity reasons will be considered as having experienced 
DLT. The DLT definitions are the following:  


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An SRC will be convened, comprised of enrolling study Investigators, Medical Monitor, and the 
Sponsor Medical Director or designee. All potentials DLTs will be reviewed by the SRC for a 
final determination and for the SRC to make recommendations regarding the study. The SRC will 
also consider AEs, particularly high-grade toxicities that may have occurred in patients in any 
treatment arm (even beyond the DLT period), when making decisions/recommendations to 
proceed with the study. The SRC will provide recommendations for study drug dosing and 
alternative dosing regimens as appropriate, not exceeding a 3-fold increment from one dose level 
to the next. The maximum dose level explored will not exceed 
 studied in the ongoing ANV419-001 study. Near the end of dose escalation, the 
statistician will also contribute to dose escalation recommendation, using the BOIN design, to 
select the MTD/RP2D.  
After completion of the 
 DLT period for each cohort, intra-patient dose escalation is 
permitted with approval of the Investigator and provided the following criteria have been met: 
 The patient has completed at least 1 treatment cycle; 
 The DLT assessment of the dose level to which the patient will be dose-escalated is complete 
and determined to be safe by the SRC; 
 The patient did not experience any AEs related to study drug(s) Grade 1 at the dose level 
prior to escalation; and 
 The patient has not required any dose reduction. 
 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Patients will receive ANV419 as monotherapy (Arms A1 and A2) or in combination with 
pembrolizumab (Arm B) or ipilimumab (Arm C) after all Screening procedures have been 
completed and eligibility has been confirmed by the Investigator. Only patients enrolled in the 
study may receive the study drug(s). Under no circumstances will the study drug(s) be used other 
than as directed within this Protocol. The 3 study drugs and the administration of each are 
described in Table TS7. 
Table TS7. 
Study Drug Administration 
Treatment
Study Part
Arm
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration/Duration
Regimen/ 
Treatment 
Period
ANV419


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Pembro
Ipi 6,7
1. 
Acetaminophen 1 g may be given to the patients as pre-medication or following the ANV419 infusion and can be used every 8 
hours based on the symptoms experienced by the patient.  
2. 
Hydration prior to and following ANV419 infusion is to be administered according to institutional guidelines. 
3. 
Dose increments will be determined by the SRC based on a synthesis of all relevant data available from all dose levels evaluated 
in this study. 
4. 
For the combination arms (Arm B and Arm C) of the study, pembrolizumab or ipilimumab will be administered first. Patients can 
receive the ANV419 infusion approximately 30 minutes after they have received the entire infusion of pembrolizumab or 
ipilimumab.  
5. 
In Arms B and C of the Dose Expansion part of the study, ANV419 will be administered at the RP2D(p) or RP2D(i), respectively, 
identified in the Combination Dose Finding part. 
6. 
Sites should make every effort to target infusion timing to be as close to 30 minutes (for pembrolizumab) or 90 minutes (for 
ipilimumab) as possible from treatment start; however, given the variability of infusion pumps from site to site, a window of ±5 
minutes is permitted. 
7. 
Ipilimumab dosing will end after 
. Ipilimumab should be permanently discontinued for patients who fail to 
complete the full treatment course w
from administration of first dose. 
8. 
Patients being treated on combination therapy with ANV419 plus ipilimumab who require discontinuation of ipilimumab due to 
toxicity may continue treatment with ANV419 after approval from the Sponsor. The reason for discontinuation must be recorded. 
Ipi = ipilimumab; IV = intravenous(ly); Pembro = pembrolizumab; 
; 
RP2D(i) = recommended Phase 2 dose for ANV419 when administered with ipilimumab; RP2D(p) = recommended Phase 2 dose for 
ANV419 when administered with pembrolizumab; SRC = Safety Review Committee.
Except during Cycles 1 and 2 in Arms B and C, study drug(s) may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle due to administrative reasons.  
Except during the DLT assessment period, if a dose cannot be administered at the foreseen 
 
 due to intercurrent medical issues unrelated to any study drug, dosing may be delayed for 
 to 4 weeks. The 
 cycle will be resumed according to the re-start date. 
Post-infusion observation – Monotherapy Dose Expansion part 
In both arms of the Monotherapy Dose Expansion part (Arms A1 and A2), all patients will be 
monitored for 90 minutes post end of infusion from Cycle 1. Patients will be monitored per 
individual site institutional standard during administration of ANV419 as monotherapy. In 
addition: 
 Vital signs will be monitored every 2 hours for the first 8 hours, for the first 2 cycles; 
 After Cycle 2, the observation period will lessen to 90 minutes post end of infusion, provided 
no additional safety concerns have been identified; 
 Patients may require observation beyond 23 hours if Grade 3 AE and/or requires medical 
intervention and prolonged medical observation. 
Note: It is optionally recommended (not mandatory) that patients stay in close proximity (as 
defined by the Investigator) to the site and are accompanied by a caregiver when possible, for 
whom accommodations will be provided. 


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Post-infusion observation – Combination Dose Finding part 
At the end of study drug(s) infusion in Cycles 1 and 2 (only) of the Combination Dose Finding 
part, all patients will undergo a 23-hour observation period. Clinical monitoring will be conducted 
per individual site institutional standards within the framework of observation required for this 
Protocol, as follows: 
 Vital signs will be monitored every 2 hours for the first 8 hours, and 20 hours post end of 
infusion; 
 After Cycle 2, the observation period will lessen to 90 minutes post end of infusion, provided 
no additional safety concerns have been identified; 
 Patients may require observation beyond 23 hours if Grade 3 AE and/or requires medical 
intervention and prolonged medical observation. 
Post-infusion observation – Combination Dose Expansion part 
In both arms of the Combination Dose Expansion part (Arms B and C), all patients will be 
monitored for 90 minutes or longer post end of infusion in Cycle 1, depending on whether 
additional safety concerns have been identified in Part 2. Patients will be monitored per individual 
site institutional standard during administration of ANV419 in combination with pembrolizumab
or ipilimumab. 
Note: It is optionally recommended (not mandatory) that patients stay in close proximity (as 
defined by the Investigator) to the site and are accompanied by a caregiver when possible, for 
whom accommodations will be provided. 
SAFETY VARIABLES: 
The safety of ANV419 as monotherapy and in combination with pembrolizumab or ipilimumab 
will be assessed by monitoring AEs (including TEAEs, DLTs [Combination Dose Finding part
only], AEs of special interest, serious AEs, immune-related AEs, and AEs leading to 
discontinuation of the study), physical examination findings (including ECOG performance 
status), clinical laboratory assessments, vital signs measurements, and electrocardiograms. AEs 
will be coded using the Medical Dictionary for Regulatory Activities and graded according to 
NCI CTCAE version 5.0. 
STATISTICAL ANALYSES: 
The Safety Population will consist of all patients who receive at least 1 dose (or partial dose) of 
study drug(s). The Safety Population will be used for safety analyses including DLT 
assessment(s).  
The Efficacy Population will consist of all patients who receive at least 1 dose of study drug, have 
at least 1 post-baseline tumor assessment, and who are part of the Monotherapy Dose Expansion 
part, Combination Dose Finding part, or the Combination Dose Expansion part. The Efficacy
Population will be used for efficacy analyses.  
The Pharmacokinetic (PK) Population will consist of all patients who receive at least 1 dose of 
study drug and have at least 1 measured concentration for at least 1 of the analytes. The PK 
Population will be used for PK analyses. 


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The Pharmacodynamic (PD) Population will consist of all patients who receive at least 1 dose of 
study drug and have at least 1 evaluable PD sample. The PD Population will be used for PD
endpoint analyses. 
Interim analysis of efficacy 
In Arm B or C, an interim analysis of the primary outcome will be performed at the end of Stage 1 
of the Combination Dose Expansion part of the study (once 12 evaluable patients have completed 
at least 1 disease evaluation or have discontinued from the study). Any treatment arm with an ORR 
20% per RECIST (ie, treatment arms with no more than 2 complete or partial responses) will be 
discontinued. 
Final analysis of efficacy 
Efficacy analysis will be conducted using the Efficacy Population. The primary outcome (ORR 
per RECIST) will be presented together with a 95% confidence interval (CI) for each treatment 
arm. Treatment arms with an observed ORR 95% CI with a lower limit above 20% and an upper 
limit above 40% will be considered for future study. All other outcomes measures will be 
summarized with the appropriate descriptive statistics. 
Analysis of safety  
In general, all safety analyses will be descriptive and presented in tabular format with appropriate 
summary statistics for the Safety Population. The impact of possible anti-ANV419 antibodies on 
safety of ANV419 will be assessed. 
Analysis of pharmacokinetics 
Plasma concentrations of ANV419 will be determined with a validated bioanalytical assay. 
Selected parameters will be calculated from plasma concentrations using noncompartmental 
analyses. Summary statistics will be generated by treatment arm as appropriate. 
PK parameters to be analyzed: 
 Systemic clearance of ANV419; 
 Volume of distribution at steady state of ANV419;  
 Area under the concentration-time curve of ANV419; and 
 Maximum observed serum concentration of ANV419. 
Analysis of pharmacodynamics  
The result, change, percent change, and maximum percent change in immunologic changes to 
selected serum cytokines and immune cell subsets in the blood and tumor microenvironment will 
be summarized descriptively. 
PD parameters to be analyzed (including, but not limited to): 
 CD3, CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366. 
Other analysis 
Clinical benefit assessment Quality of Life evaluation will be summarized using descriptive 
statistics. 


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SAMPLE SIZE DETERMINATION: 
Monotherapy Dose Expansion part 
This part of the study will use Bayesian sequential monitoring. A maximum of 15 patients will be 
enrolled and treated at each dose level arm. Arms A1 and A2 (monotherapy) will be analyzed as 
independent experiments, and also overall, and the following assumptions are made: 
 Nothing is known a priori: assume a uniform prior, ie, the true ORR could be any value 
between 0% and 100%; 
 A true ORR 6% indicates treatment failure; and 
 A true ORR 10% indicates treatment success. 
With a maximum of 15 patients in each arm, if no responses were observed, then the estimated 
true ORR would be 5.9%, with 90% CI (0.3%, 17.1%). This would be sufficient evidence to 
suggest that the treatment is unlikely to be successful. With a maximum of 30 patients overall, if 
no responses were observed, then the estimated true ORR would be 3.1%, with 90% CI 
(0.2%, 9.2%). This would be sufficient evidence to suggest that the treatment at either dose is 
unlikely to be successful. 
There is 95% certainty that the true ORR is greater than 10% if any 1 of the following are observed:
 2 responses in 3 to 7 patients;  
 3 responses in 8 to 13 patients;  
 4 responses in 14 to 19 patients; or  
 5 responses in 20 to 27 patients. 
Combination Dose Finding part 
The Combination Dose Finding part will employ BOINa to find the MTD/RP2D of Arm B 
(ANV419 in combination with pembrolizumab) and Arm C (ANV419 in combination with 
ipilimumab). For each arm, the following assumptions have been predefined for the dose 
escalation: 
 Target DLT rate of 25%; 
 Maximum of 25 patients; 
 Maximum of 9 patients treated at the same dose level; and  
 Maximum of 5 dose levels defined in TS5 to be tested. 
Patients will be enrolled and treated in cohorts of 3 patients (at least). Up to 50 patients in total 
will be enrolled for the Combination Dose Finding part.  
Combination Dose Expansion part (efficacy analysis) 
The sample size calculation is based on a Simon’s 2-stagea design and ensures that under all 
possible distributions of patients to the 2 treatment arms, there is at least 80% power to correctly 
detect an ORR 40% and at most a Type I error rate of 10% of rejecting a null hypothesis that 
ORR 20%. This results in a sample size of 12 patients randomized to each treatment arm in 


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Stage 1, followed by 13 additional patients randomized during Stage 2: a total of 25 patients per 
arm at the end of Stage 2. 
SITES: Approximately 30 sites in the United States of America and Europe 
SPONSOR: 
Anaveon AG 
Technologiepark Basel 
Hochbergerstrasse 60C 
4057 Basel 
Switzerland 
Telephone: +41 61 521 83 83
 
a. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1-10.  


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 23 
List of Tables ................................................................................................................................ 28 
List of Figures ............................................................................................................................... 29 
List of Abbreviations and Definition of Terms............................................................................. 30 
1 Introduction and Background Information ............................................................................. 33 
1.1 
Immunotherapy ............................................................................................................. 33 
1.2 
Cutaneous Melanoma .................................................................................................... 34 
1.3 
ANV419 ........................................................................................................................ 35 
1.3.1 Nonclinical Pharmacology ................................................................................ 35 
1.3.2 Nonclinical Pharmacokinetics ........................................................................... 36 
1.3.3 Toxicology ........................................................................................................ 36 
1.3.4 Clinical Experience ........................................................................................... 37 
1.4 
Rationale ........................................................................................................................ 39 
1.5 
Risk/Benefit ................................................................................................................... 40 
2 Study Objectives and Endpoints ............................................................................................. 41 
3 Study Description.................................................................................................................... 45 
3.1 
Summary of Study Design ............................................................................................ 45 
3.1.1 Part 1: Monotherapy Dose Expansion ............................................................... 46 
3.1.2 Part 2: Combination Dose Finding .................................................................... 46 
3.1.2.1 Bayesian optimal interval dose escalation guidelines ......................... 47 
3.1.3 Part 3: Combination Dose Expansion ............................................................... 50 
3.1.4 Dose-Limiting Toxicity Criteria (Applicable to Combination Dose Finding 
Part Only) .......................................................................................................... 51 
3.2 
Stopping Rules .............................................................................................................. 52 
3.3 
Safety Review Committee ............................................................................................. 52 
3.4 
Study Indication(s) ........................................................................................................ 52 
4 Selection and Withdrawal of Patients ..................................................................................... 53 
4.1 
Inclusion Criteria ........................................................................................................... 53 


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4.2 
Exclusion Criteria .......................................................................................................... 54 
4.3 
Suspension of enrollment .............................................................................................. 56 
4.3.1 Criteria for suspension of enrollment ................................................................ 56 
4.4 
Discontinuation of study treatment ............................................................................... 57 
4.5 
Reasons for End of Study and withdrawal from study .................................................. 58 
4.6 
Patients of Reproductive Potential ................................................................................ 58 
5 Study Treatments .................................................................................................................... 60 
5.1 
Treatment Groups .......................................................................................................... 60 
5.2 
Rationale for Dosing ..................................................................................................... 60 
5.2.1 Rationale for ANV419 Dosing .......................................................................... 60 
5.2.2 Rationale for Pembrolizumab Dosing ............................................................... 61 
5.2.3 Rationale for Ipilimumab Dosing ...................................................................... 61 
5.3 
Randomization and Blinding ......................................................................................... 61 
5.4 
Drug Supplies ................................................................................................................ 61 
5.4.1 Formulation and Packaging ............................................................................... 61 
5.4.2 Study Drug Preparation and Dispensing ........................................................... 62 
5.4.3 Study Drug Administration ............................................................................... 62 
5.4.3.1 Post-infusion observation – Monotherapy Dose Expansion part ........ 63 
5.4.3.2 Post-infusion observation – Combination Dose Finding part ............. 63 
5.4.3.3 Post-infusion observation – Combination Dose Expansion part ........ 64 
5.4.4 Management of Infusion-Related Reactions in the Monotherapy Arm ............ 64 
5.4.5 Dose Modification Guidelines .......................................................................... 65 
5.4.5.1 Dose Modification and Management Guidelines for adverse events 
related to ANV419 in Monotherapy Arms ......................................... 66 
5.4.5.2 Management of adverse immune-related adverse events in 
monotherapy arms ............................................................................... 70 
5.4.5.3 Management of cytokine release syndrome in monotherapy and 
combination therapy arms ................................................................... 71 
5.4.5.4 Management of adverse events in combination arms ......................... 73 
5.4.5.5 Management of infusion-related reactions for combination therapy 
arms ..................................................................................................... 82 
5.4.6 Treatment Compliance ...................................................................................... 82 
5.4.7 Storage and Accountability ............................................................................... 83 


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5.5 
Prior and Concomitant Medications and/or Procedures ................................................ 83 
5.5.1 Excluded Medications and/or Procedures ......................................................... 83 
5.5.2 Allowed Medications and/or Procedures .......................................................... 83 
5.5.3 Documentation of Prior and Concomitant Medication Use .............................. 84 
6 Study Procedures .................................................................................................................... 85 
6.1 
Tumor Measurements .................................................................................................... 85 
6.2 
Eastern Cooperative Oncology Group Performance Status .......................................... 85 
6.3 
Quality of Life Evaluation ............................................................................................. 85 
6.4 
Optional Tissue Biopsies ............................................................................................... 85 
6.5 
Pharmacokinetic Analyses ............................................................................................ 85 
6.6 
Pharmacodynamic Analyses (Immuno-Profiling and Ki67 Analysis) .......................... 86 
6.7 
Exploratory Serum Biomarker Analyses ....................................................................... 86 
6.8 
Peripheral Blood Mononuclear Cell and Cytokine Production Analyses ..................... 86 
6.9 
Tumor Mutational Burden and Circulating Tumor DNA Analyses .............................. 86 
6.10 Other Exploratory Biomarkers ...................................................................................... 87 
6.11 Immunogenicity Analyses ............................................................................................. 87 
6.12 Serology ........................................................................................................................ 88 
6.13 Sample Labeling and Storage ........................................................................................ 88 
6.13.1 Sample Labeling ................................................................................................ 88 
6.13.2 Sample Storage .................................................................................................. 88 
7 Safety Assessments ................................................................................................................. 89 
7.1 
Adverse Events .............................................................................................................. 89 
7.1.1 Adverse (Drug) Reaction .................................................................................. 90 
7.1.2 Unexpected Adverse Drug Reaction ................................................................. 90 
7.1.3 Assessment of Adverse Events by the Investigator .......................................... 90 
7.1.4 Adverse Events of Special Interest .................................................................... 91 
7.2 
Serious Adverse Events ................................................................................................. 92 
7.3 
Serious Adverse Event Reporting – Procedures for Investigators ................................ 92 
7.4 
Pregnancy Reporting ..................................................................................................... 93 
7.5 
Expedited Reporting ...................................................................................................... 93 
7.6 
Special Situation Reports .............................................................................................. 94 
7.7 
Clinical Laboratory Assessments .................................................................................. 95 


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7.8 
Vital Signs ..................................................................................................................... 95 
7.9 
Electrocardiograms ........................................................................................................ 95 
7.10 Physical Examinations .................................................................................................. 95 
8 Statistics .................................................................................................................................. 96 
8.1 
Analysis Populations ..................................................................................................... 96 
8.2 
Statistical Methods ........................................................................................................ 96 
8.2.1 Sample Size Determination ............................................................................... 96 
8.2.2 Baseline Characteristics .................................................................................... 97 
8.2.3 Interim Efficacy Analysis .................................................................................. 97 
8.2.4 Final Analysis of Efficacy ................................................................................. 97 
8.2.5 Analysis of Immunogenicity ............................................................................. 98 
8.2.6 Analysis of Safety ............................................................................................. 99 
8.2.7 Analysis of Pharmacokinetics ........................................................................... 99 
8.2.8 Analysis of Pharmacodynamics ........................................................................ 99 
8.2.9 Other Analysis ................................................................................................... 99 
9 Data Management and Record Keeping ............................................................................... 100 
9.1 
Data Management ....................................................................................................... 100 
9.1.1 Data Handling ................................................................................................. 100 
9.1.2 Computer Systems ........................................................................................... 100 
9.1.3 Data Entry ....................................................................................................... 100 
9.1.4 Medical Information Coding ........................................................................... 100 
9.1.5 Data Validation ............................................................................................... 100 
9.2 
Record Keeping ........................................................................................................... 100 
9.3 
End of Study ................................................................................................................ 101 
10 Investigator Requirements and Quality Control ................................................................... 102 
10.1 Ethical Conduct of the Study ...................................................................................... 102 
10.2 Institutional Review Board/Independent Ethics Committee ....................................... 102 
10.3 Informed Consent ........................................................................................................ 102 
10.4 Future Use of Biological Samples ............................................................................... 102 
10.5 Patient Emergency Study Contact Card ...................................................................... 103 
10.6 Study Monitoring Requirements ................................................................................. 103 
10.7 Disclosure of Data ....................................................................................................... 104 


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10.8 Retention of Records ................................................................................................... 104 
10.9 Publication Policy ....................................................................................................... 104 
10.10 Insurance and Indemnity ............................................................................................. 104 
10.11 Legal Aspects .............................................................................................................. 105 
11 Study Administrative Information ........................................................................................ 106 
11.1 Protocol Amendments ................................................................................................. 106 
12 References ............................................................................................................................. 107 
Appendix A: Schedule of Procedures ......................................................................................... 110 
Appendix B: Clinical Laboratory Analytes ................................................................................ 119 
Appendix C: Tumor Measurements and Assessment of Disease Response Using Response 
Evaluable Criteria in Solid Tumors (RECIST) 1.1 ............................................................... 121 
Appendix D: Modified Response Evaluation Criteria in Solid Tumors 1.1 for 
Immune-Based Therapeutics (iRECIST) Quick Reference .................................................. 123 
Appendix E: Examples of Sensitive Clinical Substrates for P450-Mediated Metabolism (for 
Concomitant Use in Clinical DDI Studies and/or Labeling) ................................................ 125 
Appendix F: ANV419 Safety Events .......................................................................................... 126 
Appendix G: Eastern Cooperative Oncology Group Performance Status .................................. 128 


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LIST OF TABLES 
Table 1 Study ANV419-001: Grade 3 or Higher Drug Related Treatment-Emergent Adverse 
Events .......................................................................................................................... 37 
Table 2. 
Study Objectives and Endpoints for Part 1: Monotherapy Dose Expansion .............. 41 
Table 3. 
Study Objectives and Endpoints for Part 2: Combination Dose Finding ................... 42 
Table 4. 
Study Objectives and Endpoints for Part 3: Combination Dose Expansion ............... 43 
Table 5. 
ANV419 Dose Escalation Plan for Combination Dose Finding Part (Pembrolizumab 
or Ipilimumab) ............................................................................................................ 47 
Table 6. 
Dose Escalation/De-Escalation Rule for the BOIN Design ........................................ 48 
Table 7. 
Operating Characteristics of the BOIN Design .......................................................... 50 
Table 8. 
Continuation Decision Rules for Combination Dose Expansion Part ........................ 50 
Table 9. 
Adequate Organ Function Laboratory Values ............................................................ 53 
Table 10. Study Drug Administration ......................................................................................... 62 
Table 11. Management of Allergic Reactions ............................................................................ 65 
Table 12: Management guidelines for pyrexia related to ANV419 .............................................. 67 
Table 13: Management guidelines for lymphopenia related to ANV419 ..................................... 67 
Table 14: Management guidelines for AST and/or ALT elevations with early onset related to 
ANV419 ...................................................................................................................... 68 
Table 15: Management guidelines for hepatitis related to ANV419 ............................................ 68 
Table 16: Management guidelines for “other” ANV419 related adverse events .......................... 70 
Table 17:Management of CRS per NCI CTCAE Version 5.0 ...................................................... 72 
Table 18. Dose Modification for ANV419 in Combination With Pembrolizumab .................... 75 
Table 19. Dose Modification for ANV419 in Combination With Ipilimumab .......................... 79 
Table 20 . Schedule of Procedures for Patients Enrolled in Arms A1 or A2 (Monotherapy) ... 110 
Table 21. Schedule of Procedures for Patients Enrolled in Arm B and Arm C (Combination 
Therapy) .................................................................................................................... 114 
Table 22. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Guidelines for Tumor 
Response ................................................................................................................... 122 
Table 23 Comparison Between RECIST 1.1 and iRECIST..................................................... 123 
Table 24. Examples of Sensitive Clinical Substrates for P450-Mediated Metabolism ............ 125 
Table 25. Study ANV419-001: Drug Related Treatment Emergent Adverse Events ................ 126 
Table 26. ECOG Performance Status ....................................................................................... 128 
 
 


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LIST OF FIGURES 
Figure 1. ANV419 Effect on Lymphocyte Count over Treatment Cycles ................................... 38 
Figure 2. ANV419 and Preferential Proliferation of CD8+ and NK Cells ................................... 39 
Figure 3. Study Design ................................................................................................................. 45 
Figure 4. Flowchart for Trial Conduct Using the BOIN Design .................................................. 49 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
 
Alpha 
β 
Beta 
γ 
Gamma 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIDS 
Acquired immunodeficiency syndrome 
AUC 
Area under the concentration-time curve 
BOIN 
Bayesian optimal interval 
BRAF 
B-type Raf proto-oncogene 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Systemic clearance 
CM 
Cutaneous melanoma 
Cmax 
Maximum observed serum concentration 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTA 
Clinical trial authorization 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
FDA 
Food and Drug Administration 
FoxP3 
Forkhead box P3 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HIV 
Human immunodeficiency virus 
ICANS 
Immune effector cell-associated neurotoxicity syndrome 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
iCR 
Immune complete response 
iDCR 
Immune disease control rate 
iDOR 
Immune duration of response 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IL-2R 
Interleukin-2 receptor 
IMP 
Investigational medical product 
iPFS 
Immune progression-free survival 
iPR 
Immune partial response 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
IRR 
Infusion-related reaction 
IRT 
Interactive Response Technology 
iSD 
iTTR 
Immune stable disease 
Immune Time to Response 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MEK 
Mitogen-activated protein kinase kinase enzyme 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for
Adverse Events 
NIMP 
Non-investigational medical product 
NK 
Natural killer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PEG 
Polyethylene glycol 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Definition 
PR 
Partial response 
 
 2 weeks 
 
 3 weeks 
QTcF 
Heart rate-corrected QT interval using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RP2D(i) 
Recommended Phase 2 dose for ANV419 when administered in 
combination with ipilimumab 
RP2D(p) 
Recommended Phase 2 dose for ANV419 when administered in 
combination with pembrolizumab 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T cell 
Thymus lymphocyte cell 
TEAE 
Treatment-emergent adverse event 
Treg 
TTR 
Regulatory T cell 
Time to Response 
USA 
United States of America 
Vss 
Volume of distribution at steady state 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Immunotherapy 
Activating the immune system produces durable responses in a subset of human cancers. 
Recombinant interleukin (IL)-2 (Aldesleukin),2 by directly stimulating innate and adaptive 
effector lymphocytes, is approved for the treatment of metastatic melanoma and renal cell 
carcinoma and induces durable responses and cures cancer in a significant proportion 
(approximately 10%) of patients.3,4 More recently, checkpoint inhibition has been successfully 
introduced into clinical oncology and has produced clinically impressive durable response rates 
and significant survival benefits in melanoma, renal cell carcinoma, non-small cell lung cancer 
and other tumors.5,6,7 Despite this breakthrough success of checkpoint blockade, most patients with 
advanced cancer still relapse and eventually succumb to the disease and further therapy 
improvement is therefore needed.  
The current armamentarium of immuno-stimulators is rapidly growing beyond checkpoint 
inhibitors, including novel IL-2-like therapies. The clinical usefulness of recombinant IL-2 
(Aldesleukin) has been limited because of important safety, efficacy, and logistic limitations. In 
brief, the safety profile among 525 patients treated for malignant melanoma and renal cell 
carcinoma reported hypotension (71% overall; 3% Grade 4), vomiting (50%; 1% Grade 4), 
diarrhea (65%; 2% Grade 4), thrombocytopenia (37% 1% Grade 4), bilirubinemia (40%; 2% 
Grade 4), and oliguria (63%; 6% Grade 4). Of note, serious manifestations of eosinophilia 
involving eosinophilic infiltration of cardiac and pulmonary tissues can occur following use of 
aldesleukin.2 Six of 8 deaths during treatment of 270 patients were attributed to IL-2 (2.2%).8 In 
all, this has led to a black box warning for capillary leak syndrome, which is characterized by a 
loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space 
and may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, 
myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or 
infarction, renal insufficiency, edema, and mental status changes. Therefore, IL-2 should be 
administered in a hospital with an intensive care facility and specialists skilled in cardiopulmonary 
or intensive care medicine available.  
The non-selective stimulation of anti-cancer effector cells (ie, cluster of differentiation [CD]8+ 
thymus lymphocyte cells (T cells) and natural killer [NK] cells) and immune suppressing 
regulatory T cells (Tregs) is believed to limit efficacy of Aldesleukin. The short half-life of IL-2 
requires dosing via continuous infusion or at least 3 times per day dosing for 5 to 8 days, further 
restricting its use and overall clinical usefulness.  
 
 
 
 
 
 
 
 


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1.2 
Cutaneous Melanoma 
Worldwide, about 232,100 (1.7%) cases of all newly diagnosed primary malignant cancers 
(excluding non-melanoma skin cancer) are cases of cutaneous melanoma (CM), and about 
55,500 cancer deaths (0.7% of all cancer deaths) are due to CM annually. Of the 10 leading cancer 
types (excluding basal-cell and squamous-cell carcinoma of the skin), CM was the fifth most 
common malignancy in men and the sixth most common in women in the United States of America 
(USA) in 2017. The incidence of CM has increased since the early 1970s in predominantly 
fair-skinned populations.9 
Historically, the median survival for patients with metastatic CM has been under 1 year. Treatment 
options for metastatic CM have traditionally been limited to chemotherapeutic agents such as 
dacarbazine and high-dose IL-2 immunotherapy in a small percentage of patients. In the past 
decade there has been steady progress in the development of targeted therapy and immunotherapy 
for metastatic CM.10 Using programmed death-1 (PD-1)-based treatment algorithms and targeted 
agents in B-type Raf proto-oncogene (BRAF) V600-mutant melanoma, 5-year overall survival 
(OS) rates for metastatic melanoma have increased substantially from less than 10% to up to 40% 
to 50% today in countries that have access to these innovations. However, patients with high tumor 
burden, brain metastasis, and elevated lactate dehydrogenase (LDH) still have a very poor 
prognosis (3-year survival <10%).9 
Approximately 40% of melanomas harbor the BRAF V600 mutation, leading to constitutive 
activation of the mitogen activation protein kinase signaling pathway. Dual inhibition of this 
pathway in patients with unresectable BRAFV600-mutated melanoma, using combination therapy 
with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors, confers high response 
rates and survival benefit, although efficacy, in metastatic patients, is often limited by development 
of resistance. Three combinations of targeted therapy with BRAF/MEK inhibitors have received 
Food and Drug Administration (FDA) approval in the unresectable setting (dabrafenib and 
trametinib, vemurafenib and cobimetinib, encorafenib and binimetinib), while dabrafenib and 
trametinib are also approved as adjuvant therapy following the resection of stage 3/4 melanoma. 
The oncolytic herpes virus talimogene laherparepvec is also FDA approved for the local treatment 
of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent 
after initial surgery.11 
In 2020, the first triple-therapy combining BRAF/MEK targeted and anti-programmed 
death-ligand 1 (PD-L1) immunotherapy with atezolizumab, vemurafenib and cobimetinib 
(IMspire150 study) was approved for unresectable or metastatic BRAF V600-mutated 
melanoma,12 while another trial investigating triple therapy (spartalizumab, dabrafenib and 
trametinib) missed its endpoint.13 However, toxicity was remarkable, with 79% of patients 
experiencing severe side effects and treatment discontinuation in 45%. In the adjuvant setting, 
updated data continue to support the use of either anti-PD-1 antibodies and BRAF/MEK 
inhibitors.11  
Pembrolizumab has shown clinical activity in several cancers with response rates and disease 
control rates previously not observed in immunotherapy. While impressive as a single agent in 
melanoma, with a response rate of 38% demonstrated in the Phase 1 experience,14 those patients 
that do not achieve response continue to have poor outcomes. In this context, there continues to be 
an area of unmet need in this non-responding melanoma patient population. The T cell-inflamed 
tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies 


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including therapeutic vaccines, cytokines and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) 
antibodies.15,16,17,18  
A systemic treatment that can drive a T cell response into the tumors may be CTLA-4 blocking 
antibodies. Phase 3 clinical studies evaluating the anti-CTLA-4 antibodies tremelimumab and 
ipilimumab have documented single agent response rates on the order of 10%.19,20 For both 
tremelimumab and ipilimumab, pre- and post-treatment biopsies have demonstrated a significant 
increase in CD8+ tumor-infiltrating lymphocytes in tumor lesions after anti-CTLA-4 antibody 
treatment.21,22 In some studies,23 there is also indication of modulation with the intra-tumoral 
Forkhead box P3 (FoxP3)+ Treg population; however, this has not been seen uniformly. 
In spite of these newly approved therapies, overall outlook for patients with metastatic CM remains 
dismal and the development of new effective and tolerable therapy is still needed. More 
specifically, an estimated 30% to 70% of patients do not respond to initial anti-programmed 
death 1/ligand 1 (PD-1/L1) therapy, and approximately 25% eventually progress.24,25,26,27 Thus, 
there remains a high unmet need for safe novel treatment modalities that are able to produce 
durable and deeper responses, as well as increased survival, in a greater percentage of eligible CM 
patients. 
1.3 
ANV419 
ANV419 is being developed by Anaveon AG for the treatment of multiple advanced solid tumors 
and multiple myeloma as a single agent and in combination with other immunostimulatory 
approaches. ANV419 is a stable fusion protein comprised of IL-2 fused to an anti-IL-2 monoclonal 
antibody (mAb) that sterically blocks the binding of the IL-2 to IL-2R alpha () chain. As a result, 
ANV419 is a high molecular weight IL-2 agonist which signals through the IL-2R β/γ present on 
NK cells and CD8+ T cells but shows markedly reduced signaling through the IL-2R /β/γ present 
on Tregs. ANV419 has a longer half-life relative to IL-2, shows good selectivity towards the 
expansion of NK and CD8+ T cells over Tregs, in the ongoing ANV419-001 Phase 1 study. In 
addition, the covalent linkage to IgG prolongs the half-life of ANV419, leaving target mediated 
disposition as the major driver of clearance. Compared with other novel IL-2 agents, the molecular 
characteristics of ANV419 aim to enable delivery of a higher molar equivalent of IL-2, with 
improved tolerability and safety profile, combined with a long duration of action, resulting in 
effective therapy in an outpatient setting. 
Available data for ANV419 support the hypothesis that it may potentially provide a favorable 
risk/benefit profile for patients with cancer, who can benefit from immunotherapy. 
 
1.3.1 
Nonclinical Pharmacology 
The pharmacology of ANV419 was characterized pre-clinically in protein and cell-based assays 
as well as in murine and cynomolgus monkey pharmacodynamic (PD) studies. Affinity 
measurements confirmed binding of ANV419 to the IL-2R β subunit with a dissociation constant 
comparable to recombinant IL-2 and showed absence of ANV419 binding to the IL-2R  subunit. 
In peripheral blood mononuclear cell (PBMC) in vitro stimulation experiments, this selective 
IL-2R chain binding profile translated into strongly reduced IL-2R signaling potency in Tregs 


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while comparable potency to recombinant IL-2 was maintained for CD8+ T and NK cells. 
Accordingly, in both mice and monkeys, IV bolus administration of ANV419 led to a preferential 
proliferation and expansion of CD8+ T and NK cells over Tregs in a dose-dependent manner. As 
a monotherapy, ANV419 inhibited tumor growth in well-established syngeneic mouse tumor 
models. ANV419 combination with checkpoint inhibition showed improved efficacy compared 
with single compound efficacy. 
1.3.2 
Nonclinical Pharmacokinetics 
The pharmacokinetic (PK) behavior of ANV419 was characterized in cynomolgus monkeys 
following IV bolus administration and the serum concentration-time profiles were analyzed using 
population PK modeling. A non-linear and faster apparent elimination of ANV419 from serum at 
lower doses/concentrations was observed, consistently with a target-mediated drug disposition 
phenomenon. 
 serum half-life of ANV419 is estimated at approximately 24 hours in absence 
 target-mediated drug disposition or at target saturation. Upon administration of up to 330 ug/kg 
 
. 
1.3.3 
Toxicology 
ANV419 administered IV to CD-1® International Genetic Standard mice 
 
 mg/kg/occasion as a result of pulmonary inflammation and 
 of hepatocytes. All findings noted in this study were a result of the expected 
 effect of an IL-2 fusion protein. The Highest Non-Severely-Toxic-Dose in this 
 study was 0.07 mg/kg twice weekly. 
The Good Laboratory Practices (GLP) and non-GLP studies in cynomolgus monkeys showed 
consistent findings, all related to the pharmacological effects of ANV419 as an agonistic IL-2 
fusion protein. T
 study, with the exception of the selectivity of ANV419 for cytotoxic T lymphocytes and NK cells 
 there was evidence for a dose-response over the dose range 0.03 to 0.33 mg/kg 
 with minimal pharmacological effects observed at 0.03 mg/kg and evidence for a mild systemic 
 response and effects on heart and respiratory rates at 
 mg/kg IV as a 
 of a more exaggerated pharmacological activity at this dose. The reported No 
 Adverse Effect Level in the monkey GLP toxicity study was 0.3 mg/kg. At this dose 
 concentration for males were 7680 ±842 ng/mL and 113000 ±15600 ng·h/mL, and for 
 were 7020 ±740 ng/mL and 94400 ±9800 ng·h/mL, respectively. 
No significant differences in the cytokine release potency in whole human blood were observed 
between ANV419 and recombinant IL-2. The maximal cytokine secretion levels as well as the 
responder frequencies at related doses were similar for both compounds for all cytokines.  
In summary, the nonclinical data support the design of ANV419 as a uniquely engineered “not-” 
IL-2R agonist. No unexpected effects were observed in either mice or cynomolgus monkeys and 
all findings were related to the expected pharmacology of ANV419. 
For more details on the non-clinical studies and toxicology of ANV419, please see the 
Investigator’s Brochure. 


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1.3.4 
Clinical Experience 
In the ANV419-001 (NCT04855929) Phase 1 dose finding study of ANV419, 34 patients with 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 and a range of primary 
tumor types with multiple previous lines of therapy, including immunotherapy, targeted therapy, 
and chemotherapy, have been enrolled and treated as of 07 November 2022. 
The doses of ANV419 investigated ranged from  µg/kg to 364 µg/kg, administered as a 15-minute 
 infusion once every two weeks, in 2 week cycles. The maximum tolerated dose (MTD) 
 reached at 243 µg/kg.  
Preliminary Safety profile 
ANV419 was generally well tolerated across multiple cycles, with no dose-limiting toxicities 
(DLTs) 
 to and including 243 µg/kg of ANV419. The main safety findings detected in treated 
patients (N=34) were generally low grade, transient and self-limiting. As expected with IL-2 class 
agents, all patients experienced chills and fever which were predominantly of low grade. The most 
frequent drug related TEAEs (≥10% of patients) regardless of Grade and ANV419 dose level were: 
Pyrexia (74%), chills (62%), vomiting (35%), nausea (32%), cytokine release syndrome (CRS) 
(24%), asthenia (21%), decreased appetite (21%), ALT increased (18%), AST increased (18%), 
blood bilirubin increased (18%), fatigue (18%), diarrhea (12%), hypotension (12%), myalgia 
(12%) and maculopapular rash (12%). Transient and self-limiting lymphopenias (up to Grade 4), 
resulting from mode of action related lymphocyte sequestration, were observed in all patients, 
however considered as non-clinically significant in most instances. All related events were 
generally responsive to supportive care therapy and reversible.  
Ten of 34 subjects (29%) had Grade 3 or higher drug related TEAE. The most frequent ≥Grade 3 
drug related TEAE (≥5% of subjects) were, AST increase (6%), blood creatinine increase (6%), 
lymphopenia (9%) and nausea (6%). 
 
At the dose 
 364µg/kg (above MTD), 4 patients out of 5 treated had Grade 3 or higher drug 
 TEAE: one Grade 3 pemphigoid (DLT) and Grade 3 nausea; one Grade 3 bilirubin and 
 
 increase, Grade 3 diarrhea, Grade 3 nausea and Grade 3 asthenia. A summary of all 
 related Grade 3 or higher TEAEs reported in the ongoing ANV419-001 study is presented 
. 
 
Table 1 Study ANV419-001: Grade 3 or Higher Drug Related Treatment-Emergent 
Adverse Events 
 
System Organ Class 
Preferred Term 
No Subjects (%) 
N=34
Blood and lymphatic 
system disorders
Lymphopenia 
3 (9%) 
Investigations 
ALT increase
1 (3%)
AST increase
2 (6%) 
Blood bilirubin increase
1 (3%)
Blood creatinine increase
2 (6%)
Platelet count decrease
1 (3%)
Gastrointestinal 
disorders 
Nausea 
2 (6%)
Diarrhea
1 (3%)


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Skin and subcutaneous 
tissue disorders
Pemphigoid 
1 (3%) 
Immune system 
disorders
Cytokine Release Syndrome 
1 (3%) 
General disorders and 
administration site 
conditions
Pyrexia
1 (3%)
Asthenia 
1 (3%) 
 
All drug related SAEs at doses of 
(MTD) were of low grade; 5 CRS (4 Grade 1 and 1 
Grade 2) and one pyrexia (Grade 1). All these events met SAE criteria as they required either 
hospitalization or prolongation of an existing hospitalization. 
At doses of 
and higher, an increasing inflammatory response was observed when 
compared to lower ANV419 doses with patients experiencing higher fever (with chills, CRP, LFT 
elevation and clinically non-significant drop in platelet counts, as expected with IL-2 class agents, 
although with a better tolerability compared to recombinant IL-2.  
At dose of 
, lymphopenia, resulting from lymphocyte sequestration, increased in 
duration 
 48 to at least 72 hours, with a more pronounced rebound and increased lymphocyte 
count at day 8 at subsequent cycles. This observation is reminiscent of the PD effect described 
with recombinant high dose IL-245 given three times a day for a total of 6-9 administrations (Figure 
1). 
 
Figure 1. ANV419 Effect on Lymphocyte Count over Treatment Cycles 
 
 
 
A comprehensive summary of all drugs related TEAEs reported in the ongoing ANV419-001 study is 
presented in Appendix F. 
Pharmacodynamic Effect 
Pharmacodynamic markers of target engagement have been investigated at each dose of ANV419 
and up to 
 


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 in blood is observed starting from doses of 48 µg/kg for CD8 T cells and 24 µg/kg for NK 
 
Figure 2. ANV419 and Preferential Proliferation of CD8+ and NK Cells 
 
 CD = cluster of differentiation; NK = natural killer; Treg = regulatory T cell. 
 
Preliminary Efficacy 
Among the 34 patients treated, 33 patients were evaluable for tumor response using RECIST v1.1 
Twenty patients (61%) achieved SD or better (19 SD, 1 confirmed PR). 
14/20 
patients 
(70%) 
achieved 
SD 
(13 
SD, 
1 
confirmed 
PR). 
 
1.4 
Rationale 
Checkpoint inhibitors have demonstrated durable response rates and significant survival benefit in 
melanoma, renal cell carcinoma, non-small cell lung cancer,5,6,7 and other tumors. Despite this, 
many patients experience resistance to checkpoint inhibitors and/or are unable to tolerate therapy. 
Ultimately, most patients with advanced cancer relapse and eventually succumb to the disease. 
Additional therapeutic options are needed. 
In the current study, Anaveon AG proposes to test the hypothesis that the administration of 
ANV419 as monotherapy or in combination with anti-PD-1 antibody (pembrolizumab) or 
anti-CTLA-4 antibody (ipilimumab) will generate clinical responses in patients with CM whose 
disease has progressed on anti-PD-1/anti-PD-L1 antibody or in combination (eg, anti-CTLA-4 
antibody). The study will also provide the opportunity to explore blood and tumor-based markers 
that may predict response to ANV419 as monotherapy or in combination with anti-PD-1 antibody 
or anti-CTLA-4 antibody. 


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1.5 
Risk/Benefit 
Patients with CM, and particularly those with unresectable or metastatic CM following 
anti-PD-1/anti-PD-L1 antibody treatment represent populations with high unmet need. As 
discussed in Section 1.2, an estimated 30% to 70% of patients do not respond to initial 
anti-PD-1/anti-PD-L1 therapy and approximately 25% of patients eventually progress and may 
have no other therapeutic options. Therefore, there is an urgent need to identify new targeted 
therapies and/or combination therapies to overcome current IL-2 limitations that contribute to 
significant toxicity. 
The available clinical data for ANV419 suggest ANV419 may have a favorable risk/benefit profile 
for patients with melanoma and this will be further explored in the ANV419-101 study.  
The preclinical data demonstrate that ANV419 is a uniquely engineered “not-” IL-2R agonist 
that signals preferentially through the intermediate affinity IL-2R β/γ and thus strongly stimulates 
proliferation of CD8+ T cells and NK cells while avoiding proliferation of immunosuppressive 
Tregs. 
Since ANV419 is an experimental medicine, it is possible that unforeseen, unknown, or 
unanticipated drug reactions and toxicities may occur. However, as detailed below, this Protocol 
is designed to mitigate risks to patients through a detailed plan for careful safety monitoring, 
systemic review of AEs, SAEs, and active pharmacovigilance review to assess for safety signals 
or trends. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints for Part 1: Monotherapy Dose Expansion, Part 2: Combination 
Dose Finding, and Part 3: Combination Dose Expansion are provided in Table 2, Table 3, and 
Table 4. 
Table 2. Study Objectives and Endpoints for Part 1: Monotherapy Dose Expansion 
Part 1: Monotherapy Dose Expansion – Arms A1 and A2
Primary Objectives
Primary Endpoints
Evaluate the efficacy of ANV419
ORR (CR + PR), as defined by RECIST v1.1 (hereinafter, RECIST).
Secondary Objectives 
Secondary Endpoints 
To characterize the tumor 
response according to modified 
RECIST v1.1 criteria for 
immune-based therapeutics 
(iRECIST)
Tumor response in terms of objective response rate (ORR: CR + PR) 
assessed by iRECIST
Expand evaluation of efficacy of 
ANV419
- 
DOR (per RECIST) and iDOR (per iRECIST[1]) measured from first 
response until disease progression; 
- 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD), PFS, 
iPFS, and OS; 
- 
Median TTR; and 
-
Median iTTR.
Evaluate the safety of ANV419
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs;  
- 
irAEs; 
- 
AESIs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and 
physical examination.
Explore immunogenicity after 
exposure to ANV419
Incidence of immunogenicity as indicated by ADA.
Exploratory Objectives
Exploratory Endpoints
Explore the changes in the tumor 
microenvironment before and 
after adding ANV419 as 
monotherapy 
Changes in immunological biomarker expression from baseline and post 
treatment tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, 
CD3, CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, IL-
6, IL-10); and 
-
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.
Analysis of changes in baseline ctDNA and at specified timepoints on 
therapy and after therapy. 
Analysis of single nucleotide polymorphisms, germline DNA for 
genome-wide association studies, analysis of T cell receptor repertoire, 
epigenetic markers, soluble CD25, and soluble PD-1/PD-L1. 
1. 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for the response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
AE = adverse event; AESI = adverse event of special interest; CD = cluster of differentiation; CR = complete response; ctDNA = 
circulating tumor deoxyribonucleic acid; DCR = disease control rate; DOR = duration of response; ECG = electrocardiogram; FoxP3 
= Forkhead box P3; iCR = immune complete response; iDCR = immune disease control rate; iDOR = immune duration of response; 
IFNγ = interferon gamma; IL = interleukin; iPFS = immune progression-free survival; iPR = immune partial response; irAE = immune-
related adverse event; iRECIST = immune Response Evaluation Criteria in Solid Tumors; iSD = immune stable disease; 
iTTR = immune time to response; ORR = objective response rate; OS = overall survival; PD-1 = programmed death-1; 
PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PR = partial response; RECIST = Response Evaluation Criteria 
in Solid Tumors; SAE = serious adverse event; SD = stable disease; T cell = thymus lymphocyte cell; TNF = tumor necrosis factor; 
TTR = time to response; v1.1 = version 1.1.


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Table 3. Study Objectives and Endpoints for Part 2: Combination Dose Finding 
Combination Dose Finding – Combination Therapy Arms (Arms B and C) 
Primary Objectives
Primary Endpoints
Evaluate the safety and 
tolerability and determine the 
RP2D of ANV419 in combination 
with pembrolizumab
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs; 
- 
TEAEs; 
- 
DLTs; 
- 
AESIs; 
- 
irAEs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and 
physical examinations.
Evaluate the safety and 
tolerability and determine the 
RP2D of ANV419 in combination 
with ipilimumab
Secondary Objectives 
Secondary Endpoints 
Evaluate PK and PD of ANV419 
in combination with 
pembrolizumab or ipilimumab
PK endpoints in serum: 
- 
CL of ANV419; 
- 
Vss of ANV419; 
- 
AUC of ANV419; and 
- 
Cmax of ANV419. 
 
PD endpoints in peripheral blood: including, but not limited to, CD3, CD4, 
CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366.
Explore immunogenicity after 
exposure to ANV419 in 
combination with pembrolizumab 
or ipilimumab
Incidence of immunogenicity as indicated by ADA.
Evaluate the efficacy of ANV419 
in combination with 
pembrolizumab or ipilimumab
ORR (CR + PR), as defined by RECIST.
Expand evaluation of efficacy of 
ANV419 in combination with 
pembrolizumab or ipilimumab
DOR (per RECIST) and iDOR (per iRECIST[1]) measured from first 
response until disease progression; 
PFS, iPFS, and OS; 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD),  
Median TTR; and 
Median iTTR.
Evaluate clinical benefit in quality 
of life after exposure to ANV419 
in combination with 
pembrolizumab or ipilimumab
Change in QoL at baseline and every 12 weeks while receiving ANV419 via 
QoL evaluations:  
- 
EQ-5D-5L; and 
-
QLQ-C30.
Exploratory Objectives
Exploratory Endpoints
Explore the changes in the tumor 
microenvironment before and 
after adding ANV419 as 
monotherapy and in combination 
with pembrolizumab or 
ipilimumab
Changes in immunological biomarker expression from baseline and post 
treatment tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, 
CD3, CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, 
IL-6, IL-10); and 
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.
Analysis of changes in baseline ctDNA and at specified timepoints on 
therapy and after therapy.


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Analysis of single nucleotide polymorphisms, germline DNA for 
genome-wide association studies, analysis of T cell receptor repertoire, 
epigenetic markers, soluble CD25, and soluble PD-1/PD-L1.
Table 3. 
Study Objectives and Endpoints for Part 2: Combination Dose Finding 
(Continued) 
ADA = anti-drug antibodies; AE = adverse event; AESI = adverse event of special interest; AUC = area under the concentration-time 
curve; CD = cluster of differentiation; CL = systemic clearance; Cmax = maximum observed serum concentration; CR = complete 
response; ctDNA = circulating tumor deoxyribonucleic acid; DLT = dose-limiting toxicity; ECG = electrocardiogram; EQ-5D-5L = 
Euro-QoL 5 dimension 5 level; FoxP3 = Forkhead box P3; IFNγ = interferon gamma; IL = interleukin; irAE = immune-related adverse 
event; ORR = objective response rate; PD = pharmacodynamic(s); PD-1 = programmed death-1; PD-L1 = programmed death-ligand 
1; PK = pharmacokinetic(s); PR = partial response; QLQ-C30 = quality of life core 30; QoL = quality of life; RECIST = Response 
Evaluation Criteria in Solid Tumors; RP2D = recommended Phase 2 dose; SAE = serious adverse event; T cell = thymus lymphocyte 
cell; TEAE = treatment-emergent adverse event; TNF = tumor necrosis factor; Vss = volume of distribution at steady state.
 
Table 4. 
Study Objectives and Endpoints for Part 3: Combination Dose Expansion 
Part 3: Combination Dose Expansion – Combination Therapy Arms (Arms B and C)
Primary Objectives 
Primary Endpoints 
Evaluate the efficacy of ANV419 
in combination with 
pembrolizumab or ipilimumab 
ORR (CR + PR), as defined by RECIST.
Secondary Objectives 
Secondary Endpoints 
Expand evaluation of efficacy of 
ANV419 in combination with 
pembrolizumab or ipilimumab
- 
DOR (per RECIST) and iDOR (per iRECIST[0]) measured from first 
response until disease progression; 
- 
DCR (DCR = CR + PR + SD), iDCR (iDCR = iCR + iPR + iSD), PFS, 
iPFS, and OS; 
- 
Median TTR; and 
-
Median iTTR.
Part 3: Combination Dose Expansion – Combination Therapy Arms (Arms B and C) 
Secondary Objectives 
Secondary Endpoints 
Evaluate the safety of ANV419 in 
combination with pembrolizumab 
or ipilimumab 
Incidence, frequency, and severity of AEs including the following: 
- 
SAEs;  
- 
irAEs; 
- 
AESIs; 
- 
AEs leading to discontinuation of the study; and 
- 
Changes from baseline in laboratory parameters, vital signs, ECGs, and 
physical examination.
Evaluate clinical benefit in 
quality of life after exposure to 
ANV419 in combination with 
pembrolizumab or ipilimumab
Change in QoL at baseline and every 12 weeks while receiving ANV419 via 
QoL evaluations:  
- 
EQ-5D-5L; and 
-
QLQ-C30.
Explore immunogenicity after 
exposure to ANV419 in 
combination with pembrolizumab 
or ipilimumab
Incidence of immunogenicity as indicated by ADA.
Exploratory Objectives 
Exploratory Endpoints 
Explore the changes in the tumor 
microenvironment before and 
after adding ANV419 in 
combination with pembrolizumab 
or ipilimumab
Changes in immunological biomarker expression from baseline and post 
treatment tumor and liquid biopsies, including: 
- 
Immune cell counts, immunophenotyping (including, but not limited to, 
CD3, CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366); 
- 
Cytokine production (including, but not limited to, IFNγ, IL-2, TNF, IL-
6, IL-10); and 
-
Immunohistochemistry (including, but not limited to, CD8, CD4, Ki67).
Analysis of mutations in the tumor and analysis of tumor mutational burden.


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Analysis of changes in baseline ctDNA and at specified timepoints on 
therapy and after therapy.
Analysis of single nucleotide polymorphisms, germline DNA for 
genome-wide association studies, analysis of T cell receptor repertoire, 
epigenetic markers, soluble CD25, and soluble PD-1/PD-L1.
 
Table 4. 
Study Objectives and Endpoints for Part 3: Combination Dose Expansion 
(Continued) 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for the response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
AE = adverse event; AESI = adverse event of special interest; CD = cluster of differentiation; CR = complete response; 
ctDNA = circulating tumor deoxyribonucleic acid; DCR = disease control rate; DOR = duration of response; 
ECG = electrocardiogram; EQ-5D-5L = Euro-QoL 5 dimension 5 level; FoxP3 = Forkhead box P3; iCR = immune complete 
response; iDCR = immune disease control rate; iDOR = immune duration of response; IFNγ = interferon gamma; 
IL = interleukin; iPFS = immune progression-free survival; iPR = immune partial response; irAE = immune-related adverse 
event; iRECIST = immune Response Evaluation Criteria in Solid Tumors; iSD = immune stable disease; iTTR = immune time 
to response; ORR = objective response rate; OS = overall survival; PD-1 = programmed death-1; PD-L1 = programmed 
death-ligand 1; PFS = progression-free survival; PR = partial response; QLQ-C30 = quality of life core 30; QoL = quality of 
life; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SD = stable disease; 
T cell = thymus lymphocyte cell; TNF = tumor necrosis factor; TTR = time to response.
 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a multi-site, open-label, randomized, parallel arm, Phase 1/2 adaptive study to evaluate the 
efficacy and safety of ANV419 as a monotherapy and in combination with pembrolizumab or 
ipilimumab in patients aged 18 years or older with advanced CM who have previously been treated 
with at least 1 line of standard of care immunotherapy, including an anti-PD-1/anti-PD-L1 
antibody. 
The 4 following treatment arms will be included in this study: 
 Arm A1: 
 (108 µg/kg, Q2W); 
 Arm A2: 
 (243 µg/kg, Q2W); 
 Arm B: 
 in combination with pembrolizumab (Keytruda); and 
 Arm C: 
 in combination with ipilimumab (Yervoy). 
There will be up to 3 separate parts in this study: Part 1: Monotherapy Dose Expansion with 
patients randomized to receive infusion of ANV419 (
 µg/kg [Arm A1] or 243 µg/kg [Arm A2]) 
 2 weeks. If Part 1 is successful, Part 2: Combination Dose Finding with patients randomized 
to Arms B and C with infusion of ANV419 
 3 weeks, and finally, Part 3: Combination Dose 
Expansion with patients randomized to Arms B and C (see Figure 3). A total of up to 130 patients 
are planned to be enrolled in the study: a maximum of 30 patients in the Monotherapy Dose 
Expansion part, a maximum of 50 patients in the Combination Dose Finding part, and a maximum 
of 50 patients in the Combination Dose Expansion part. Randomization in the Monotherapy Dose 
Expansion part and Combination Dose Expansion part will be stratified by BRAF mutation status. 
In the Combination Dose Expansion part, the number of patients within each arm will be 
determined by pre-defined decision rules presented in Table 5. 
 
Figure 3. Study Design 
 
* = If ANV419 monotherapy is successful, the combination portion will be initiated. 
** = Dose escalation increment is decided by the SRC until RP2D of ANV419 per arm is identified. 
*** = Arm not meeting pre-specified ORR criteria may be stopped early after Stage 1. 
In the Combination Dose Finding part, patients will be manually randomized to Arm B or Arm C. In the Monotherapy Dose 
Expansion part and the Combination Dose Expansion part, patients will be randomized by IRT into Arms A1 or A2 and Arms B 
or C, respectively. 


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Ipi = ipilimumab; IRT = Interactive Response Technology; ORR = objective response rate; Pembro = pembrolizumab; 
R = randomization; RP2D = recommended Phase 2 dose; SRC = Safety Review Committee.  
All patients will be assessed for response using Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (hereinafter, RECIST) and computed tomography (CT) imaging, which will 
occur every  weeks (±7 days) from baseline until Cycle 13 (for the monotherapy arm) or every 9 
 (±7 days) from baseline until Cycle 7 (for combination therapy arms), using the same 
modality as used for baseline imaging until progressive disease per RECIST and immune RECIST 
(iRECIST), withdrawal of consent, or initiation of a new anticancer therapy. Treatment decision 
will be based on local assessment. All images will be collected and stored centrally for potential 
central analysis. 
 Cycle 13 (for the monotherapy arms) or Cycle 7 (for the combination 
 arms), scans should be performed every 12 weeks (±7 days) from the previous assessment. 
The study will also assess other clinical parameters including progression free survival (PFS) and 
will provide the opportunity to explore blood- and tumor based markers that may predict response 
to ANV419 as monotherapy or in combination with anti-PD-1 or anti CTLA-4 antibodies. 
3.1.1 
Part 1: Monotherapy Dose Expansion 
The Monotherapy Dose Expansion part (Arms A1 and A2) will be a parallel group part with a 
Bayesian sequential monitoring analysis28 and up to 15 patients per arm. This part will establish 
the efficacy and safety of ANV419 as monotherapy.  
Two doses of ANV419 will be explored: 
 µg/kg and 243 µg/kg based on data collected in the 
ongoing Phase 1 ANV419-001 study at a frequency of 
 2 weeks (Q2W). Treatment with 
ANV419 as a monotherapy can continue for 
 months within the current Protocol in the absence 
of disease progression or unacceptable toxicity and in the absence of data from Arms A1 and A2 
showing an unfavorable risk/benefit profile for patients on ANV419 monotherapy.  
Decision making on whether to continue the study beyond the Monotherapy Dose Expansion part, 
and the total number of patients recruited to this part, will be based on Bayesian sequential 
monitoring. The study will be stopped at the end of this part in the case of an unfavorable 
risk/benefit profile for ANV419 monotherapy. This includes observing a total of 0 of 30 responses 
from the 2 monotherapy arms combined (a strong signal that ANV419 does not induce a response) 
and/or report of any safety issues that might stop the trial. There is 95% certainty that the true 
objective response rate (ORR) is greater than 10% if we observe any 1 of the following: 
 2 responses in 3 to 7 patients;  
 3 responses in 8 to 13 patients;  
 4 responses in 14 to 19 patients; or  
 5 responses in 20 to 27 patients. 
Response (complete response [CR] or partial response [PR]) will be assessed locally at each 
disease evaluation. 
3.1.2 
Part 2: Combination Dose Finding 
This part will only be initiated following approval of a substantial amendment supporting the 
ANV419 starting dose in the combination part. The submission will include data from ANV419-
001 Study and from Part 1 of this trial, and occurat any time when at least 2 responses have been 
observed in the Monotherapy Dose Expansion part. 


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The Combination Dose Finding part will be comprised of 2 arms (Arms B and C) that will identify 
a recommended Phase 2 dose (RP2D) for ANV419 in each arm when administered in combination 
with pembrolizumab (Arm B) or ipilimumab (Arm C) at the prescribed dosing. The number of 
patients recruited to each arm will be between 6 and 25 patients depending on the number of dose 
increments possible. A minimum of 6 patients will be treated at RP2D. The patients from the 
Combination Dose Finding part will not be randomized into the Combination Dose Expansion 
part. 
Dosing of ANV419 when administered in combination with pembrolizumab (Arm B) or 
ipilimumab (Arm C) will occur as shown in Table 5, with a dose of ANV419 currently planned to 
start at 
 every 3 weeks (Q3W). Patients in the Combination Dose Finding part will be 
treated with a minimum of 24 hours interval between patients to allow for monitoring of acute 
toxicities. Dose level 1, as shown in Table 5, will be reviewed by the Safety Review Committee 
(SRC) per the safety evaluations and the SRC will make dose increment recommendations at each 
dose level, not exceeding 3-fold increment from on dose level to the next. The maximum dose 
level explored will not exceed the 
 dose of ANV419 monotherapy studied in the ongoing 
 study. The DLT period for the Combination Dose Finding part will last for 21 days 
 cycle), beginning at Cycle 1 Day 1 and ending at the end of Cycle 1 Day 21 prior to Cycle 2 
 1. For details on the DLT criteria for the Combination Dose Finding part of this study, see 
 3.1.4. 
Table 5. ANV419 Dose Escalation Plan for Combination Dose Finding Part 
(Pembrolizumab or Ipilimumab) 
Dose Level
ANV419 Dose
Pembrolizumab Dose or 
Ipilimumab Dose
Frequency
1
2
3
4
5
Note: ANV419 will be administered by IV infusion over 15 minutes (+5 minutes).  
1. 
Dose increments will be determined by the SRC based on a synthesis of all relevant data available from all dose levels 
evaluated in this study, not exceeding a 3-fold increment from one dose level to the next. The maximum dose level explored 
will not exceed the 
 dose of ANV419 monotherapy studied in the ongoing ANV419-001 study. 
IV = intravenous(ly); 
 = every 3 weeks SRC = Safety Review Committee; TBD = to be determined.
3.1.2.1 
Bayesian optimal interval dose escalation guidelines 
In the Combination Dose Finding part, dose escalation will follow the Bayesian optimal interval 
(BOIN)29 design with the following predefined rules to find the MTDs/RP2Ds of ANV419 in 
combination with pembrolizumab or ipilimumab to be used in the efficacy analysis: 
 Target DLT rate of 25%; 
 Maximum of 25 patients; 
 Maximum of 9 patients treated at the same dose level; and  
 Maximum of 5 dose levels defined in Table 5 to be tested. 
As shown in Figure 4, the BOIN29 design uses the following rules, optimized to minimize the 
probability of incorrect dose assignment, to guide dose escalation/de-escalation: 


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 If the observed DLT rate at the current dose is 
, escalate the dose to the next higher dose 
level; 
 If the observed DLT rate at the current dose is 
, de-escalate the dose to the next lower 
dose level; and 
 Otherwise, stay at the current dose. 
The steps to implement the BOIN design are described as follows: 
1. Patients in the first cohort with a cohort size of 3 patients are treated at dose level 1; 
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according 
to the rule displayed in Table 6; and 
Note: If none of the actions (ie, escalation or de-escalation) is triggered, treat the new patients 
at the current dose. 
3. Repeat step 2 until the maximum sample size of 25 is reached or a stopping rule is met, or if 
the number of evaluable patients treated at the current dose reaches 9 and the decision 
according to Table 6 is to stay at the current dose. 
After the study is completed, the MTD will be selected based on isotonic regression as specified 
by Liu and Yuan.29 Specifically, the MTD will be selected as the dose for which the isotonic 
estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher 
dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose 
level when the isotonic estimate is greater than or equal to the target toxicity rate. 
Table 6. Dose Escalation/De-Escalation Rule for the BOIN Design 
 
 
 


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Figure 4. Flowchart for Trial Conduct Using the BOIN Design 
BOIN = Bayesian optimal interval; DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
Operation characteristics 
Table 7 shows the operating characteristics of the trial design and based on 1000 simulations of 
the trial using R package “BOIN” (BOIN v2.7.0.0).30 The operating characteristics show that the 
design selects the true MTD, if any, with high probability and allocates more patients to the dose 
levels with DLT rate closest to the target of 
 


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Table 7. Operating Characteristics of the BOIN Design 
3.1.3 
Part 3: Combination Dose Expansion 
The Combination Dose Expansion part of the study will be separate from the Combination Dose 
Finding part and will evaluate the safety and efficacy of ANV419 in combination with 
pembrolizumab (Arm B) or ipilimumab (Arm C). This Combination Dose Expansion part will 
consist of 2 stages. In Stage 1, 12 patients will be randomized by interactive response technology 
(IRT) into each arm. At the end of this stage, an interim analysis will be performed to assess 
continuation of treatment arms into Stage 2 (see Table 8). In Stage 2, eligible patients will be 
randomized to the remaining treatment arms, determined at the interim analysis. Recruitment will 
continue until 25 patients have been randomized to a treatment arm. 
Table 8. Continuation Decision Rules for Combination Dose Expansion Part 
Treatment Arm Accrual
Discontinue if the 
Number of Responses is 
Discontinue Criterion in 
Terms of ORR 
Continue if the Number 
of Responses is at Least
Stage 1 (n=12)
2
Observed ORR 20%
3
ORR = objective response rate.
Dosing for ANV419 in the combination arms (Arms B and C) in the Combination Dose Expansion 
part will be based on the RP2Ds for ANV419 determined in the Combination Dose Finding part, 
ie, the RP2D for ANV419 when administered in combination with pembrolizumab (hereinafter, 
RP2D[p]) and the RP2D for ANV419 when administered in combination with ipilimumab 
(hereinafter, RP2D[i]).  
Treatment with ANV419 in combination with pembrolizumab can continue for 24 months within 
the current Protocol in the absence of disease progression or unacceptable toxicity.  


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Treatment with ANV419 in combination with ipilimumab can continue up to a maximum of 
4 cycles, per the approved label (United States Prescribing Information and Summary of Product 
Characteristics). If ipilimumab-related AEs occur, ipilimumab can be discontinued at any time. 
Once a patient has completed the maximum of 4 
 of ipilimumab allowed, they will continue 
 ANV419 at the dose enrolled as monotherapy Q3W and may continue for 24 months in 
 absence of disease progression or unacceptable toxicity. Beyond 24 
3.1.4 
Dose-Limiting Toxicity Criteria (Applicable to Combination Dose Finding Part Only) 
A DLT is defined as any of the treatment-emergent AEs (TEAEs) listed below, as defined by the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 5.0, occurring during the DLT period (
 1 Day 1 through Cycle 1 Day 21) and the AE 
is not reasonably attributed to the patient’s underlying disease, other medical conditions, or 
concomitant medications. To be DLT evaluable, the patient must complete 
 1 and receive 
 second dose of the study drug(s). Any patient that discontinues the study before the DLT period 
 over (Cycle 1 Day 1 through Cycle 1 Day 21) for reason other than DLT or any event that renders 
 patient non evaluable for DLT will be replaced. Patient who experiences a delay of Cycle 2 
 longer than 7 days for toxicity reasons will be considered as having experienced DLT. The 
DLT definitions are the following:  
An SRC will be convened, comprised of enrolling study Investigators, Medical Monitor, and the 
Sponsor Medical Director or designee. All potentials DLTs will be reviewed by the SRC for a final 
determination and for the SRC to make recommendations regarding the study. The SRC will also 


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consider AEs, particularly high-grade toxicities that may have occurred in patients in any treatment 
arm (even beyond the DLT period), when making decisions/recommendations to proceed with the 
study. The SRC will provide recommendations for study drug dosing and alternative dosing 
regimens as appropriate, not exceeding a 3-fold increment from one dose level to the next. The 
maximum dose level explored will not exceed the 
 dose of ANV419 monotherapy studied in 
the ongoing ANV419-001 study. Near the end of dose escalation, the statistician will also 
contribute to dose escalation recommendation, using the BOIN design, to select the MTD/RP2D. 
After completion of the 
 DLT period for each cohort, intra-patient dose escalation is 
permitted with approval of the Investigator and provided the following criteria have been met: 
 The patient has completed at least 1 treatment cycle; 
 The DLT assessment of the dose level to which the patient will be dose-escalated is complete 
and determined to be safe by the SRC; 
 The patient did not experience any AEs related to study drug(s) Grade 1 at the dose level 
prior to escalation; and 
 The patient has not required any dose reduction. 
3.2 
Stopping Rules 
Treatment of individual patients may be stopped under defined circumstances as outlined in 
Section 4.4. 
3.3 
Safety Review Committee 
An SRC will be established to monitor safety aspects of the trial and make recommendations to 
Anaveon and Medpace about trial conduct to ensure patient safety and scientific validity.  
The SRC Charter will further describe membership and responsibilities of the SRC. 
3.4 
Study Indication(s) 
ANV419 is being developed for treatment of unresectable or metastatic CM following at least 
1 line of standard of care immunotherapy, including an anti-PD-1 and/or anti-PD-L1 antibody. 
 
 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
Population 
Patients with unresectable or metastatic CM with measurable disease, whose disease has 
progressed following or on at least 1 line of standard of care immunotherapy (on anti-PD-1, 
anti-PD-L1, and/or CTLA-4 antibody treatment). 
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Must provide written informed consent for the study; 
2. Must be able to comply with the Protocol as judged by the Investigator; 
3. Are 18 years of age on day of signing informed consent; 
4. Have histologically confirmed Stage 3 (unresectable) or Stage 4 (metastatic) CM, as per the 
American Joint Committee on Cancer staging system, eighth edition; 
5. Have documented radiological progression on prior systemic therapy; 
6. Have previously received anti-PD-1/L1 as monotherapy or in combination. A maximum of 2 
prior lines of systemic therapy is allowed for BRAF wild-type disease and a maximum of 3 
prior lines of systemic therapy is allowed for BRAFV600 positive disease; 
Note: Adjuvant treatment is considered as a line of therapy only if patient experienced relapse/ 
progression on therapy or within 6 months from adjuvant therapy completion; 
7. Have measurable disease based on RECIST; 
8. Have a performance status of 0 or 1 on the ECOG Performance Status; 
9. Have adequate organ functions as defined in Table 9: 
Table 9. 
Adequate Organ Function Laboratory Values 
System
Laboratory Value
Hematological
ANC
1500/µL
Platelets
100,000/µL
Hemoglobin
9 g/dL or 4.96 mmol/L
Renal
Measured or calculated1 CrCl (GFR can also 
be used in place of CrCl)
30 mL/min 
Hepatic
Serum total bilirubin OR direct bilirubin
1.5 × ULN OR 1.5 × ULN for patients with total bilirubin 
levels 1.5 × ULN; direct bilirubin 1.5 × ULN for patients with 
Gilbert’s syndrome
AST (SGOT) or ALT (SGPT)
2.5 × ULN OR 5 × ULN for patients with liver metastases
Albumin
2.5 g/dL
1. 
CrCl should be calculated per Cockcroft-Gault equation. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine 
clearance; GFR = glomerular filtration rate; SGOT = serum glutamic oxalacetic transaminase; SGPT = serum glutamic pyruvic 
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10. Female patients of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative (urine or serum) pregnancy test within 72 hours prior to study 
Day 1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required and must be negative for the patient to be eligible; 
11. Female patients who are not postmenopausal, and who have not undergone surgical 
sterilization, must agree to use highly effective methods of contraception during the treatment 
period and for 6 months after the last dose of study drug. They must also agree not to donate 
eggs (ova, oocytes) during the same timeframe; and 
12. Male patients with partners of childbearing potential must agree to use highly effective 
methods of contraception and barrier contraception (condom) during the treatment period and 
for 6 months after the last dose of study drug. They must also agree not to donate sperm during 
the same timeframe. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Have received investigational agent (including investigational device) within 4 weeks or an 
interval of 5 half-lives of the respective investigational agent prior to study Day 1, 
whichever is longer, with the exclusion of an anti-PD-1/anti-PD-L1 antibody given as either 
a single agent or non-CTLA-4 antibody containing combination (eg, anti-lymphocyte-
activation gene 3 antibody); 
2. Have a known hypersensitivity to ANV419 or to any of the excipients, such as sucrose, 
histidine or polysorbate 80. For combination arms only: Have hypersensitivity to 
pembrolizumab or ipilimumab or any of their excipients;  
3. For combination arms only: Have previously discontinued ipilimumab, pembrolizumab, or any 
other PD-1/PD-L1 inhibitors due to unacceptable drug-related toxicity (defined as toxicities 
that required second line immunosuppression, ie, not controlled by steroids alone); 
4. Have an LDH level of 2 × upper limit of normal; 
5. Have not recovered (ie, Grade 1 or at baseline with the exception of alopecia or fatigue [up 
to Grade 2 allowed]) from AEs resulting from prior immunotherapies. Patients who have 
autoimmune AEs controlled by replacement therapy (ie, hypothyroidism) due to previous 
treatment are eligible provided replacement therapy has been initiated and toxicity has returned 
to Grade 1; 
6. Have not recovered (ie, Grade 1 or at baseline) from toxicities due to a previously 
administered prior chemotherapy, targeted small molecule therapy, or radiation therapy; 
Note: If the patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study drug. Major surgery 
is defined as any surgery requiring entrance into a body cavity (eg, chest, abdomen, or brain), 
organ removal, normal anatomy alteration, or joint replacement. Minor surgery is defined as 
any surgery in which skin, mucosa, or connective tissue sections are altered (eg, biopsy, 
cataract, endoscopic procedures, etc). 
7. Have been diagnosed with uveal/ocular or mucosal melanoma; 


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8. Have a known additional malignancy (including all in-situ carcinoma) that is progressing or 
requires active treatment within ≤2 years prior to enrollment. Exceptions include basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin that have undergone potentially 
curative therapy or in situ cervical cancer or patients who completed cancer-directed therapy 
and have no evidence of disease; 
9. Have active central nervous system metastases and/or carcinomatous meningitis. Patients with 
previously treated brain metastases may participate provided they are stable (without evidence 
of progression by imaging for at least 4 weeks prior to study Day 1 and any neurologic 
symptoms have returned to baseline or have been stable for at least 7 days), have no evidence 
of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
study drug. This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability; 
10. Have a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 
days prior to study Day 1; 
11. Are receiving systemic steroid 10 mg of prednisone daily or equivalent or any other 
immunosuppressive medication at any dose level. Local steroid therapies (eg, otic, ophthalmic, 
intra-articular, or inhaled medications) are acceptable; 
12. Have an active autoimmune disease that has required systemic treatment in the past 2 years (ie, 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment; 
13. Have evidence of active, non-infectious pneumonitis; 
14. Have active (measurable) and uncontrolled (unresponsive to current therapy) infectious disease 
(bacterial, fungal, viral, or protozoic); 
15. Have a history of an acute coronary event (eg, myocardial infarction) within 3 months prior to 
study Day 1, uncontrolled and symptomatic coronary artery disease or congestive heart failure 
New York Heart Association Class III/IV; 
16. Have an average QTcF interval 470 msec at Screening; 
17. Have a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the full 
duration of the study, or it is not in the best interest of the patient to participate, in the opinion 
of the treating Investigator; 
18. Have known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study;  
19. Are pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the Screening Visit through 6 months after the last dose of 
study drug; 
20. Are known to be human immunodeficiency virus (HIV) positive (or tests positive for HIV 1 
or 2 at Screening), unless the following criteria are met: 
a. CD4+ lymphocyte count 350 µL; 


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b. Had no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infections within the past 12 months; 
c. Have been on established anti-retroviral therapy for at least 4 weeks; and 
d. Have an HIV viral load of 400 copies/mL prior to study Day 1. 
Note: Patients on strong cytochrome P450 (CYP)3A4 inhibitors or strong CYP3A4 
inducers must be switched to an alternate effective anti-retroviral therapy regimen prior to 
study treatment or are excluded if regimen prior to study Day 1 cannot be altered. 
21. Have uncontrolled hepatitis B infection or hepatitis C infection;  
Note: Patients with hepatitis B (positive hepatitis B surface antigen) who have controlled 
infection (serum hepatitis B virus DNA by polymerase chain reaction that is below the limit of 
detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with 
controlled infections must undergo periodic monitoring of hepatitis B virus DNA.  
Note: Patients with hepatitis C (positive hepatitis C virus antibody) who have controlled 
infection (undetectable hepatitis C virus RNA by polymerase chain reaction either 
spontaneously or in response to a successful prior course of anti-hepatitis C virus therapy) are 
permitted. 
22. Have received a live vaccine within 30 days of study Day 1; or 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
23. For combination arms only: Have received solid organ or hematopoietic stem cell transplant. 
4.3 
Suspension of enrollment 
Adverse events and serious adverse events (SAEs) are expected to occur frequently in this study 
based on the patient population being accrued and the nature of the advanced malignancy. As a 
result, there is no specific incidence rate of SAEs that will define a stopping rule. Instead, regular 
systematic review of SAEs will serve as the basis for enrolment suspension or prematurely 
stopping of the study.  
4.3.1 
Criteria for suspension of enrollment 
In any case, the study will be paused and the Investigators, Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), regulatory agencies, and SRC will be promptly 
informed if any patient develops, in the dose expansion parts (Part 1 and Part 3), any of the 
following events assessed to be related to study drug by the Investigator and/or SRC: 
• 
Life-threatening (Grade 4) toxicity that is unexpected and/or unmanageable (ie, does not 
resolve to Grade 3 or lower within 7 days) 
• 
Death   
The SRC will be urgently convened to review the safety data and make recommendations for 
potential changes in the study conduct (e.g. permanent discontinuation, dose reduction of a 
treatment in the combination arm or adaptation of the safety monitoring measures). If enrollment 
suspension is triggered due to an AE suspected to be related to ANV419, the enrollment in the 


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study will be paused. However, if the enrollment suspension is triggered due to a known toxicity 
of pembrolizumab or ipilimumab, or suspected synergistic toxicity in only one of the tested 
combination therapy arm, the monotherapy arm and the other combination therapy arm will still 
proceed if toxicity is not observed. 
Should enrollment in the study or in one treatment arm be suspended, the study will not be restarted 
until all parties (SRC and Sponsor) have agreed to the course of action to be taken and the 
IRBs/IECs have been notified. 
4.4 
Discontinuation of study treatment  
Discontinuation of a patient from study treatment may occurfor any of the following reasons: 
 The patient or legal representative (such as a parent or legal guardian) withdraws consent; 
 Confirmed radiographic disease progression; 
Note: A patient may be granted an exception to continue on treatment with confirmed 
radiographic disease progression if clinically stable or clinically improved. Such cases should 
be discussed by the Investigator or treating physician with the Sponsor. 
Note: In certain circumstances, a patient experiencing disease progression per RECIST without 
clinical deterioration may be allowed to continue on treatment if the Investigator considers it 
in the patient’s best interest and in agreement between the Investigator and Sponsor. If repeated 
tumor assessment within 4 to 8 weeks confirms progressive disease, the patient will need to be 
discontinued permanently from treatment. 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the Protocol; 
 Any SAE, clinically significant AE, DLT, severe laboratory abnormality, intercurrent illness, 
or other medical condition which indicates to the Investigator that continued participation is 
not in the best interest of the patient; 
 Patients who meet Hy’s law will be discontinued from treatment; 
 Pregnancy; 
 Requirement of prohibited concomitant medication; 
 Patient failure to comply with Protocol requirements or study-related procedures; 
 The patient is lost to follow-up; or 
 Termination of the study by the Sponsor or the regulatory authority. 
Patients who discontinue for reasons noted above other than progressive disease will have 
post-treatment follow-up for disease status until disease progression, initiation of a non-study 
cancer treatment, withdrawal of consent, or lost to follow-up. In addition, each patient, irrespective 
of disease progression, will be followed for survival by telephone (or public records when allowed 
as per local regulation) until death or study termination whichever occurs first. Study staff should 
make every effort to complete the full panel of assessments scheduled for the End of Study Visit 
in addition to disease evaluation as noted above (
 730 [24 months] OR 30 days since last 


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dose of study drug). The reason for patient withdrawal must be documented in the electronic case 
report form (eCRF). 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
Any patient in the Combination Dose Finding part that does not complete the DLT period for 
reason other than DLT or that is not DLT evaluable will be replaced. 
4.5 
Reasons for End of Study and withdrawal from study 
Patients may withdraw consent at any time for any reason or be dropped from the study at the 
discretion of the Investigator should any untoward effect occur. In addition, a patient may be 
withdrawn by the Investigator or the Sponsor if enrollment into the study is inappropriate, the 
study plan is violated, or for administrative and/or other safety reasons. 
Reasons for end of study and patient withdrawal from the study could be any of the following: 
 Withdrawal of consent by the patient; 
 Lost to follow-up; 
 Death; or 
 Study termination by Sponsor. 
The study will be discontinued or terminated in case of an unacceptable risk, any relevant toxicity, 
or a negative change in the risk/benefit assessment. This might include the occurrence of AEs for 
which the character, severity, or frequency is new in comparison to the existing risk profile. In 
addition, any data deriving from other clinical studies or toxicology studies which negatively 
influence the risk/benefit assessment might cause discontinuation or termination of the study. 
4.6 
Patients of Reproductive Potential 
Pregnancy and breastfeeding are exclusion criteria for this study. It is important that female 
patients and the female partners of male patients do not become pregnant during the study and for 
a recommended period of 6 months following the last dose of ANV419. Pregnancy tests for all 
female patients of childbearing potential will be performed as shown in the Schedule of Procedures 
(Appendix A). If a planned pregnancy test reveals a start of pregnancy, the patient will be 
withdrawn from the study. 
A female patient of childbearing or reproductive potential is defined as any female who has 
experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at the 
appropriate age; eg, greater than 45 years). 
Female patients of childbearing potential must agree to use highly effective methods of 
contraception during the treatment period and for 6 months after the last dose of study drug. They 
must also agree not to donate eggs (ova, oocytes) during the same timeframe. 
Male patients with partners of childbearing potential must agree to use highly effective methods 
of contraception and barrier contraception (condom) during the treatment period and for 6 months 
after the last dose of study drug. They must also agree not to donate sperm during the same 
timeframe. 


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A highly effective method of contraception is defined as a method that can achieve a failure rate 
of less than 1% per year when used consistently and correctly, and that is considered to be a highly 
effective birth control method. Such methods include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal); 
 Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, or implantable);a 
 Intrauterine devicea intrauterine hormone-releasing systema and bilateral tubal occlusion;a  
 Vasectomized partner;a,b and 
 Sexual abstinence.c 
The double-barrier method (synthetic condoms; diaphragm; or cervical cap with spermicidal foam, 
cream or gel), periodic abstinence (such as calendar, symptothermal, or post-ovulation), 
withdrawal (coitus interruptus), lactational amenorrhea method, and spermicide only are NOT 
acceptable as highly effective methods of contraception. 
Female patients of childbearing potential and contraception methods are defined per the 
2020 Clinical Trial Facilitation Group recommendations.31 
Female patients who become pregnant must report to the Investigator and be removed from the 
study immediately. Male patients whose female partners become pregnant will not be removed 
from the study but must report to the Investigator. The Sponsor or Investigator will follow-up on 
the pregnancy until 8 weeks after delivery to assess for congenital defects. 
 
a. Contraception methods that in the context of the 2020 Clinical Trial Facilitation Groups recommendations are considered to 
have low user dependency. 
b. A vasectomized partner is a highly effective birth control method provided that the vasectomized partner is the sole sexual 
partner of the female patient of childbearing potential study participant and that the vasectomized partner has received medical 
assessment of the surgical success.  
c. In the context of the 2020 Clinical Trial Facilitation Group recommendations, sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
The 4 following treatment arms will be included in this study: 
 Arm A1: 
 (108 µg/kg, Q2W); 
 Arm A2: 
 (243 µg/kg, Q2W); 
 Arm B: 
 (Q3W) in combination with pembrolizumab (Keytruda); and 
 Arm C: 
 (Q3W) in combination with ipilimumab (Yervoy). 
5.2 
Rationale for Dosing 
5.2.1 
Rationale for ANV419 Dosing 
A
 monotherapy is being studied in the ongoing ANV419-001 Study with, as of 07 
 2022, doses of ANV419 at Q2W cycle ranging from 3 µg/kg to 364 µg/kg. The regimen 
 been generally well tolerated in patients with cancer across all dose levels and cycles,. Two 
 were observed at dose of 364 µg/kg and the MTD was reached at 243 µg/kg.  
 
 monotherapy) of the Monotherapy dose expansion part, ANV419 will be 
 IV, Q2W at the dose of 108 µg/kg (Arm A1) and 243 µg/kg (Arm A2). Depending 
 the outcome of ANV419-001 Study, additional doses might be explored in future substantial 
 
 ANV419 was well tolerated at doses ranging from 3 µg/kg to 243 µg/kg (MTD). 
 noticeable increase in the inflammatory response to ANV419 was observed starting from 
 of 108 µg/kg, with patients experiencing more chills, higher fever, CRP peak, more 
  
 the 34 patients treated, 33 patients were evaluable for tumor response with 20 
 (61%) achieving SD or better (19 SD, 1 confirmed PR). At ANV419 doses ≥108 
 14/20 patients (70%) achieved SD or better (13 SD, 1 confirmed PR), with a 
 dose-response effect when looking at overall tumor shrinkage on target lesions 
 dosing. A PR per RECIST v1.1 was reported at first response assessment (Week 6) 
 a patient with metastatic NSCLC, progressing after one line of therapy, including a CPI, 
 an ANV419 dose of 243 µg/kg.  
 effect following ANV419 administration was observed on immune 
 cells in the blood at Cycle 1, starting from 3 and 6 µg/kg in NK cells and CD8 T 
 respectively, with cell proliferation reaching a plateau at doses of 48 µg/kg for CD8 
 cells and 24 µg/kg for NK cells, while a dose-dependent effect was observed with Tregs.  
 
 in combination with pembrolizumab or ipilimumab, respectively) of 
 Combination Dose Finding part of the study, the current planned starting dose of ANV419 is 
 µg/kg. This dose might be revised once Study ANV419-001 has completed and will be 
 in a substantial protocol amendment prior to Part 2 initiation. The starting dose will 
 for a margin of safety for dose increments. Dose increments not exceeding 3-fold increment 


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 one dose level to the next will be determined by the SRC based on a synthesis of all relevant 
 available from all dose levels evaluated in this study. 
5.2.2 
Rationale for Pembrolizumab Dosing 
The dose amount for pembrolizumab will be based on the approved package insert per 
United States Prescribing Information and Summary of Product Characteristics32 and the European 
Medicines Agency-approved label; 200 mg IV Q3W. 
5.2.3 
Rationale for Ipilimumab Dosing 
The dose amount required to prepare ipilimumab will be determined based on the patient’s weight 
in kilograms and per the approved package insert33 and the European Medicines Agency-approved 
label; 3 mg/kg IV Q3W. 
5.3 
Randomization and Blinding 
Patients enrolled in the Monotherapy Dose Expansion part will be randomized by IRT and 
stratified by BRAF mutation status into Arms A1 or A2 on Cycle 1 Day 1. 
Patients enrolled in the Combination Dose Finding part will be manually randomized into Arm B 
or Arm C on Cycle 1 Day 1. Steps for assigning the randomization number are as follows: The 
Clinical Operations team/trained individuals will use the pre-generated randomization number lists 
to find the next available randomization number and assign it to the patient. The team will then 
use the randomization number to obtain the treatment assignment from the pre-generated 
randomization scheme provided by the Biostatistics team. The Clinical Operations team will 
maintain and complete the randomization schemes throughout the course of study. 
Patients enrolled in the Combination Dose Expansion part will be randomized by IRT and stratified 
by BRAF mutation status into Arms B or C on Cycle 1 Day 1.  
For the Combination Dose Expansion part, following the interim analysis at the end of Stage 1, if 
1 treatment arm is removed from Stage 2 (leaving only 1 treatment arm open for enrollment), 
randomization by IRT will no longer be required and eligible patients will be enrolled into the 
remaining treatment arm, provided there are sufficient slots remaining. 
This is an open-label study. No blinding is required. 
5.4 
Drug Supplies 
5.4.1 
Formulation and Packaging 
ANV419 is a stable fusion protein comprised of IL-2 fused to an anti-IL-2 mAb that sterically 
blocks the binding of the IL-2 to IL-2R-alpha (CD25). The ANV419 investigation product is a 
liquid, colorless, clear formulation with no visible particles, containing 2.5 mg/mL ANV419 
protein, 20 mM histidine, 8% (w/v) sucrose, and 0.02% (w/v) PS80, pH 6.0. ANV419 is stored at 
-20°C (±5°C) and thawed by leaving at room temperature (15°C to 25°C) for approximately 1 hour 
and then further diluted into normal saline. 
All ANV419 vials should be visually inspected for particulate matter and discoloration prior to 
preparation. Vials should not be used if the solution is cloudy, discolored, or contains extraneous 
or considerable particulate matter.  


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For formulation and packaging information on pembrolizumab and ipilimumab, please refer to the 
Pharmacy Manual and package inserts.32,33 
5.4.2 
Study Drug Preparation and Dispensing 
Instructions for the preparation and dispensation of ANV419, pembrolizumab, and ipilimumab are 
described in the Pharmacy Manual. 
5.4.3 
Study Drug Administration 
Patients will receive ANV419 as monotherapy (Arms A1 and A2) or in combination with 
pembrolizumab (Arm B) or ipilimumab (Arm C) after all Screening procedures have been 
completed and eligibility has been confirmed by the Investigator. Only patients enrolled in the 
study may receive the study drug(s). Under no circumstances will the study drug(s) be used other 
than as directed within this Protocol.  
The 3 study drugs and the administration of each are described in Table 10. 
Table 10. Study Drug Administration 
Treatment
Study Part
Arm
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration/Duration
Regimen/ 
Treatment 
Period
ANV419
Pembro
Ipi6,7


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1. 
Acetaminophen 1 g may be given to the patients as pre-medication or following the ANV419 infusion and can be used 
every 8 hours based on the symptoms experienced by the patient. Hydration prior to and following ANV419 infusion is to 
be administered according to institutional guidelines. 
2. 
Dose increments will be determined by the SRC based on a synthesis of all relevant data available from all dose levels 
evaluated in this study. 
3. 
For the combination arms (Arm B and Arm C) of the study, pembrolizumab or ipilimumab will be administered first. 
Patients can receive the ANV419 infusion approximately 30 minutes after they have received the entire infusion of 
pembrolizumab or ipilimumab.  
4. 
In Arms B and C of the Combination Dose Expansion part of the study, ANV419 will be administered at the RP2D(p) or 
RP2D(i), respectively, identified in the Combination Dose Finding part. 
5. 
Sites should make every effort to target infusion timing to be as close to 30 minutes (for pembrolizumab) or 90 minutes 
(for ipilimumab) as possible from treatment start; however, given the variability of infusion pumps from site to site, a 
window of ±5 minutes is permitted. 
6. 
Ipilimumab dosing will end after  treatment cycles. Ipilimumab should be permanently discontinued for patients who fail 
 complete the full treatment course within 4 cycles (12 weeks) from administration of first dose. 
7. 
Patients being treated on combination therapy with ANV419 plus ipilimumab who require discontinuation of ipilimumab 
due to toxicity may continue treatment with ANV419 after approval from the Sponsor. The reason for discontinuation must 
be recorded. 
Ipi = ipilimumab; IV = intravenous(ly); Pembro = pembrolizumab; 
 = every 2 weeks; Q3W = every 3 weeks; 
RP2D(i) = recommended Phase 2 dose for ANV419 when administered with ipilimumab; RP2D(p) = recommended Phase 2 
dose for ANV419 when administered with pembrolizumab; SRC = Safety Review Committee.
Except during Cycles 1 and 2 in Arms B and C, study drug(s) may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle due to administrative reasons.  
Except during the DLT assessment period, if a dose cannot be administered at the foreseen 
 
interval due to intercurrent medical issues unrelated to any study drug, dosing may be delayed for 
up to 
. The 
 cycle will be resumed according to the re-start date. 
5.4.3.1 
Post-infusion observation – Monotherapy Dose Expansion part 
In both arms of the Monotherapy Dose Expansion part (Arms A1 and A2), all patients will be 
monitored for 90 minutes post end of infusion from Cycle 1. Patients will be monitored per 
individual site institutional standard during administration of ANV419 as monotherapy. In 
addition: 
 Vital signs will be monitored every 2 hours for the first 8 hours, for the first 2 cycles 
 After Cycle 2, the observation period will lessen to 90 minutes post end of infusion, provided 
no additional safety concerns have been identified; 
 Patients may require observation beyond 23 hours if Grade 3 AE and/or requires medical 
intervention and prolonged medical observation. 
Note: It is optionally recommended (not mandatory) that patients stay in close proximity (as 
defined by the Investigator) to the site and are accompanied by a caregiver when possible, for 
whom accommodations will be provided. 
Based on emerging data, the SRC may still decide that it is in the best interest of the patients to 
add or remove monitoring measures or observation durations, or mandate hospitalization.  
5.4.3.2 
Post-infusion observation – Combination Dose Finding part 
At the end of study drug(s) infusion in Cycles 1 and 2 (only) of the Combination Dose Finding 
part, all patients will undergo a 23-hour observation period. Clinical monitoring will be conducted 
per individual site institutional standards within the framework of observation required for this 
Protocol, as follows: 


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 Vital signs will be monitored every 2 hours for the first 8 hours, and 20 hours post end of 
infusion; 
 After Cycle 2, the observation period will lessen to 90 minutes post end of infusion, provided 
no additional safety concerns have been identified; 
 Patients may require observation beyond 23 hours if Grade 3 AE and/or requires medical 
intervention and prolonged medical observation. 
5.4.3.3 
Post-infusion observation – Combination Dose Expansion part 
In both arms of the Combination Dose Expansion part (Arms B and C), all patients will be 
monitored for 90 minutes or longer post end of infusion from Cycle 1, depending on whether 
additional safety concerns have been idenfitied in Part 2. Patients will be monitored per individual 
site institutional standard during administration of ANV419 in combination with pembrolizumab 
or ipilimumab. 
Note: It is optionally recommended (not mandatory) that patients stay in close proximity (as 
defined by the Investigator) to the site and are accompanied by a caregiver when possible, for 
whom accommodations will be provided. 
5.4.4 
Management of Infusion-Related Reactions in the Monotherapy Arm 
Acute or delayed infusion-related reactions (IRRs) may occur with any IV administered antibody 
and may therefore be seen with ANV419. Patients must be monitored for any acute reaction during 
ANV419 administration. Following study drug infusion, patients in both arms of the Monotherapy 
Dose Expansion part (Arms A1 and A2) and Combination Dose Expansion part (Arms B and C) 
will be monitored for 90 minutes or longer post end of infusion from Cycle 1. Patients will be 
monitored per individual site institutional standard during administration of ANV419. IRRs may 
initially manifest as erythema, pruritus, fever, or chills and progress to an anaphylactic-type 
reaction. It is recommended to interrupt the infusion if there are any early signs of an 
immune-related reaction and assess the patient. If symptoms resolve without treatment, the 
infusion may resume at half the rate and continue if no further reaction. For Grade 3 reactions, 
the infusion must stop, and the event discussed with the study Medical Monitor or designee. The 
Investigator should also discuss premedication with Medical Monitor or designee. 
Symptoms of any IRRs that occur during the observation period after completion of the infusion 
should be reported in the eCRF and treated according to guidelines listed in Table 11. Any 
immune-related reaction Grade 1 will be evaluated by the SRC and guidance for the subsequent 
treatment regimen of the individual patient (eg, inclusion of premedication, interruption, or 
discontinuation of dosing schedule) and current and subsequent dosing cohort will be discussed 
with the Investigators and implemented as per SRC recommendation. 
Allergic (hypersensitivity) reactions that occur during or after study drug administration should be 
treated according to the guidelines listed in Table 11. 
 
 
 


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Table 11. Management of Allergic Reactions 
Grade of Allergic 
Reaction
Treatment 
Grade 1 
Transient flushing or 
rash, drug fever 38°C 
(100°F)
Remain at bedside and monitor patient until recovery of symptoms.
Grade 2 
Intervention and infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics); 
prophylactic medications 
indicated for 24 hours.
- 
Stop the ANV419 infusion. 
- 
Begin an IV infusion of normal saline and treat the patient with diphenhydramine 
50 mg IV (or equivalent) and/or acetaminophen 500 to 1000 mg PO. 
- 
Remain at bedside and monitor patient until resolution of symptoms. 
 
Corticosteroid therapy may also be administered as appropriate.  
 
If the infusion is interrupted: 
- 
Restart the infusion at half the rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate.  
- 
Monitor patient closely. 
If symptoms recur: 
- 
The infusion should be discontinued and no further ANV419 will be 
administered at that visit. Administer diphenhydramine 50 mg IV and remain at 
bedside and monitor the patient until resolution of symptoms.  
- 
Premedication will be instituted in patients who experience an allergic reaction 
to study drug.
Grade 3 
Prolonged (eg, not 
rapidly responsive to 
symptomatic treatment 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates). 
 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated.
- 
Immediately discontinue infusion of ANV419. Begin an IV infusion of normal 
saline, and treat the patient as follows: 
- 
Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed.  
- 
Patient should be monitored until the Investigator is comfortable that the 
symptoms will not recur. 
 
For Grade 3 or any Grade 4 allergic reaction: 
- 
ANV419 will be permanently discontinued for prolonged Grade 3 or any Grade 
4 allergic reaction.  
- 
Patients may not continue to receive reference therapy in the absence of disease 
progression and/or intolerable AEs. 
- 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. 
Remain at bedside and monitor patient until recovery from symptoms.
AE = adverse event; IV = intravenous(ly); NSAID = nonsteroidal anti-inflammatory drug; PO = orally.
5.4.5 
Dose Modification Guidelines 
AEs (both serious and non-serious) potentially related to ANV419, pembrolizumab, or ipilimumab 
may represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose.  
If a patient experiences TEAEs that may be related to ANV419 alone or in combination with 
pembrolizumab or ipilimumab, ANV419 doses might be reduced if applicable, interrupted, or 
permanently discontinued and all changes must be reported in the Case Report Form (CRF). All 
Grade 3 AEs considered possibly, probably, or definitely related to study drug(s) must be 


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discussed with the Investigator and Sponsor. During Cycle 1, dose interruption should be avoided 
if a patient has not experienced a Grade 2 TEAE related to study drug. In subsequent cycles, dose 
interruptions and/or discontinuation are permissible following discussion between the Investigator 
and the Sponsor or designee. 
 
5.4.5.1 
Dose Modification and Management Guidelines for adverse events related to 
ANV419 in Monotherapy Arms 
General principles 
Common adverse events that have been reported with ANV419 include, but are not limited to 
pyrexia, liver enzyme elevations, lymphopenia, nausea/vomiting, and low-grade CRS. Appropriate 
supportive care or pre-medication is recommended to manage ANV419 related side effects, and 
to maintain ANV419 dose-intensity.  
For patients enrolled in Arm A1 (
 µg/kg), dose reduction is not permitted but modification of 
infusion rate and/or dose delay is allowed in the event of ANV419 related toxicities. For patients 
enrolled in Arm A2 (
 µg/kg), dose reduction to 
 µg/kg is permitted in addition to 
modification of infusion rate and/or dose delay. Dose re-escalation of ANV419 to the randomized 
dose can be considered for AEs that are self-limiting and under close monitoring. If re-escalation 
is not tolerated, then ANV419 should be reinstated at reduced dose. 
Treatment may be delayed for up to  weeks (14 days) to allow for resolution of ANV419 related 
toxicities and for up to  weeks (28 days) for non-ANV419 related/unexpected toxicities (i.e., hip 
fracture). If treatment cannot be resumed within this time frame, the patient will be permanently 
discontinued from study.  
The section below provides specific guidelines for the management of related ANV419 toxicities. 
The recommendations are not intended to serve as rigid guidelines or to replace clinical judgement. 
Pyrexia  
Episodes including recurring episodes of pyrexia are observed in patients receiving ANV419. 
Pyrexia may be accompanied with chills. Pyrexia typically presents 4 to 6 hours post ANV419 
infusion and lasts between 1 and 4 days. Some patients are experiencing pyrexia on each cycle, 
others only on one cycle, not necessarily the first one. Pyrexia and chills typically resolve with 
standard supportive treatment. 
To minimize the pyrexia in patients with ANV419, anti-pyretic treatment (e.g., paracetamol or 
acetaminophen) should be administered shortly after ANV419 infusion or as pre-medication and 
repeated every 8 hours as needed.   
 
 
 
 
 


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Table 12: Management guidelines for pyrexia related to ANV419 
Pyrexia 
Recommended management 
Dose modification 
First occurrence, or 
recurrent pyrexia 
 Consider premedication with 
paracetamol/acetaminophen 
if not implemented 
 Exclude other reasons for 
pyrexia 
 Administer anti-pyretic 
treatment with NSAID 
and/or 
acetaminophen/paracetamol 
 Encourage oral hydration 
Withhold ANV419 until < Grade 
1; continue at same dose  
Recalcitrant (refractory) 
pyrexia 
 Consider adding oral 
corticosteroids  
 
If pyrexia cannot be 
successfully managed to a 
tolerable level: permanently 
discontinue if 
 
 dose reduce to 162 
 if Arm A2 (243 µg/kg)
 
Cytokine release syndrome 
For management guidelines of cytokine release syndrome (CRS), refer to Table 17 further below. 
 
Lymphopenia 
ANV419 induces transient lymphopenia assumed related to lymphocyte redistribution and 
sequestration from the peripheral blood. This is an expected pharmacodynamic effect of ANV419 
and was not associated with any increase in infection, or other clinical sequalae. In all cases, the 
observed lymphopenia was self-limiting with lymphocyte count rebounding around 
 4 and a 
dose dependent increase of lymphocyte expansion over time. Patients with prolonged or persistent 
lymphopenia should be thoroughly investigated for alternative etiologies than ANV419 related. 
Table 13: Management guidelines for lymphopenia related to ANV419 
CTCAE v5.0 
Recommended management 
Dose modification 
Any grade
None
No dose modification 
Note: for prolonged or persistent lymphopenia, alternative etiologies of lymphopenia should be 
excluded
 
AST and/or ALT elevations with early onset (Cycle 1-2) 
Transient elevation of hepatic transaminases are observed with ANV419 and are considered to 
occur in the context of IL-2 mediated AEs. The transient elevations are usually asymptomatic, 
mild or moderate in severity, typically not associated with increased total bilirubin and alkaline 
phosphatase, resolve spontaneously without treatment, and are predominantly occurring in the first 
two cycles. For AST and/or ALT elevations beyond cycle 2, and for AST/ALT elevations in the 


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context of total bilirubin increase, follow the adverse event management guidance for hepatitis 
(Table 15). 
Table 14: Management guidelines for AST and/or ALT elevations with early onset related to 
ANV419  
 
Recommended management 
Dose modification 
AST or ALT  
> 3 but ≤ 5 × ULN  
 LFT monitoring: Repeat lab 
every 3 days 
 If no improvement within 7 
days, initiate treatment with 
steroids 
 Consider imaging for 
obstruction 
 Exclude non-inflammatory 
etiologies
Withhold ANV419 until ≤ Grade 
1 or baseline; continue at same 
dose 
AST or ALT  
> 5 × but ≤ 8 × ULN 
 LFT monitoring: Repeat lab 
every 3 days 
 If no improvement within 7 
days, initiate treatment with 
steroids 
 Consider adding non-
corticosteroid 
immunotherapy
Withhold ANV419 until ≤ Grade 
1 or baseline; continue at same 
dose 
AST or ALT  
> 8 × ULN 
 LFT monitoring: Repeat lab 
every 1-2 days 
 If no improvement within 7 
days, initiate treatment with 
steroids 
 Consider adding non-
corticosteroid 
immunotherapy 
 Consult gastroenterologist 
Consider permanent 
discontinuation of ANV419 
 
Hepatitis 
Table 15: Management guidelines for hepatitis related to ANV419  
(adapted from the ASCO management guidelines for Immune-Related Adverse Events; J Clin 
Oncol2021:36 4073-4126). 
CTCAE v5.0 
Recommended management 
Dose modification 
Grade 1 
Asymptomatic (AST or 
ALT > ULN to 3.0 × 
ULN and/or total 
bilirubin > ULN to 1.5 × 
ULN
 Close monitoring (1-2 × 
weekly) 
 Exclude alternate etiologies 
(e.g., viral hepatitis, alcohol 
hepatitis) 
Continue ANV419 at same dose 


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Grade 2 
Asymptomatic (AST or 
ALT > 3.0 to ≤ 5.0 × 
ULN and/or total 
bilirubin > 1.5 to ≤ 3.0 × 
ULN) 
 Stop unnecessary 
medication and any potential 
hepatotoxic drugs 
 Consider administration of 
steroids if no improvement 
in 3-5 days 
 Increase monitoring 
frequency to every 3 days 
 Consider adding 
mycophenolate mofetil if no 
improvement after 3 days 
 Consider hepatology consult 
for Grade 2 and above
Withhold ANV419 until ≤ Grade 
1; continue at same dose 
 
Grade 3 
AST or ALT 5.0-20.0 × 
ULN and/or total 
bilirubin 3-10 × ULN, 
OR 
symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis; and 
reactivation of chronic 
hepatitis
 Start steroids 1-2 mg/kg 
methylprednisolone or 
equivalents 
 Consider liver biopsy 
 Monitor labs daily  
Permanently discontinue 
ANV419 
Grade 4  
AST or ALT > 20.0 × 
ULN and/or total 
bilirubin > 10 × ULN 
OR decompensated liver 
function 
 Consider adding 
methylprednisolone 2 
mg/kg/d equivalents 
Permanently discontinue 
ANV419 
Note: Combination of AEs suggestive of drug induced liver injury (DILI), with hepatocellular 
injury (AST or ALT > 3.0 × ULN) accompanied by evidence of impaired hepatic function (total 
bilirubin elevation > 2 × ULN), in the absence of evidence of initial biliary obstruction (i.e., 
significant elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), see FDA guidance, should lead to permanent discontinuation from treatment.  
 
 
 
 
 
 


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Other adverse events 
For other adverse events deemed as clinically significant and for which no specific guidelines are 
provided, the following dose modifications should be followed (Table 16).  
Table 16: Management guidelines for “other” ANV419 related adverse events  
CTCAE v5.0 
Dose modification 
Grade 1 
Continue at the same dose of ANV419
Grade 2  
If tolerable: Continue at the same dose of ANV419; 
If intolerable: withhold ANV419 until ≤ Grade 1 or baseline; 
reinstate ANV419 at the same dose
Grade 3 
Withhold ANV419 until ≤ Grade 1 or baseline; 
1st occurrence: reinstate ANV419 at the same dose 
2nd occurrence or if not manageable: permanently discontinue if 
 A1 (108 µg/kg); dose reduce to 162 µg/kg if Arm A2 (243 
 
3rd occurrence: permanently discontinue ANV419
Grade 4 
Permanently discontinue ANV419
 
 
5.4.5.2 
Management of adverse immune-related adverse events in monotherapy arms 
Investigators should monitor patients for potential irAEs. Once an AE is detected, it should be 
followed until resolution. An irAE can occur shortly after the first dose of ANV419 or several 
months after the last dose. For clinical management of irAEs, Investigators should follow the 
consensus guidelines provided by National Comprehensive Cancer Network,34 American Society 
of Clinical Oncology,35 and European Society for Medical Oncology36,37 . 
 
 


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5.4.5.3 
Management of cytokine release syndrome in monotherapy and combination therapy 
arms 
CRS clinically manifests when large numbers of lymphocytes (B lymphocyte cells, T cells, and/or 
NK cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) become activated 
and release inflammatory cytokines. CRS has classically been associated with therapeutic mAb 
infusions, most notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), anti-CD20 (rituximab), and 
the CD28 super-agonist, TGN1412. In these settings, symptom onset typically occurs within 
minutes to hours after the infusion begins. CRS has also been reported following administration 
of bi-specific antibodies for leukemia, infusion of haploidentical mononuclear cells to patients 
with refractory leukemia, and adoptive immunotherapies for cancer, most notably T cells 
engineered to express chimeric antigen receptors.38 
It is important to distinguish CRS from infection, tumor lysis syndrome, primary phagocyte 
lymphohistiocytosis/macrophage activation syndrome, hypersensitivity/allergic reaction(s), or 
other inflammatory disorders. Additional tests such as autoimmune serology may be used to 
determine a possible immunogenic etiology. 
The study will be conducted in sites experienced in immune-oncology clinical studies including 
the management of CRS. Patients will be monitored for signs and symptoms of CRS for all cycles 
of treatment with ANV419. Following study drug(s) infusion during dose escalation (the 
Combination Dose Finding part), all patients will undergo a 23-hour observation period. Clinical 
monitoring will be conducted per individual sites institutional standards within the framework of 
observation required for this Protocol, including monitoring of vital signs every 2 hours for the 
first 8 hours, and 20 hours post end of infusion in Cycles 1 and 2 (only). After Cycle 2, the 
observation period will lessen to 90 minutes post end of infusion, provided no additional safety 
concerns have been identified. Safety observation measures may be added or removed, at the 
discretion of the SRC, upon review of all safety data for the study. Patients may require observation 
beyond 23 hours if Grade 3 AE and/or requires medical intervention and prolonged medical 
observation. In both arms of the Monotherapy Dose Expansion part (Arms A1 and A2) and 
Combination Dose Expansion part (Arms B and C), all patients will be monitored for 90 minutes 
or longer post end of infusion from Cycle 1, depending on whether additional safety concerns have 
been identified in Part 2 . Patients will be monitored per individual site institutional standard during 
administration of ANV419 in combination with pembrolizumab or ipilimumab. It is optionally 
recommended (not mandatory) that patients stay in close proximity to the site and are accompanied 
by a caregiver when possible, for whom accommodations will be provided. Based on emerging 
data, the SRC may still decide that it is in the best interest of the patients to increase monitoring 
or observation durations, or mandate hospitalization. 
Grading of CRS should follow the criteria specified in Table 17. 
 
 


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Table 17: Management of CRS per NCI CTCAE Version 5.0 
Grade 
Treatment 
Grade 1:  
Fever with or 
without 
constitutional 
symptoms
- 
Vigilant supportive care. 
- 
Additional diagnostic testing should be performed to rule out differential diagnoses. If an 
infection cannot be ruled out with certainty, start of an empiric antibiotic therapy should 
be considered. 
- 
Treat fever and neutropenia if present, monitor fluid balance, administer anti-pyretics 
and analgesics as needed. 
- 
All patients with early signs of CRS should be regularly evaluated for signs of further 
deterioration. 
-
No actions or hold ANV419 treatment until symptoms subside.
Grade 2: 
-Hypotension 
responding to 
fluids 
-Hypoxia 
responding to 
40% O2
-
Vigilant supportive care. 
- 
Hold study drug(s). Restart once CRS resolves to Grade 1.  
- 
For subsequent infusions, increase infusion duration and consider premedication with 
antihistamines such as Benadryl and an H2 blocker. 
 
Hypoxia:  
- 
Supplemental oxygen. 
- 
Tocilizumab or siltuximab ± corticosteroids and supportive care, as recommended for the 
management of hypotension. 
 
Hypotension: 
- 
IV fluid bolus of 500 to 1000 mL of normal saline. 
- 
Can give a second IV fluid bolus if SBP remains <90 mmHg. 
- 
Tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV for the treatment of hypotension that 
is refractory to fluid boluses; tocilizumab can be repeated after 6 hours if needed. 
If hypotension persists after 2 fluid boluses and anti-IL-6 therapy: 
- 
Start vasopressors, consider hospitalization, obtain echocardiogram, and initiate other 
methods of hemodynamic monitoring. 
- 
In patients at high-risk or if hypotension persists after 1 to 2 doses of antiIL6 therapy, 
dexamethasone can be used at 10 mg IV every 6 hours. 
- 
Manage fever and constitutional symptoms as in Grade 1. 
 
Organ toxicity: 
- 
Symptomatic management of organ toxicities, as per standard guidelines. 
- 
Consider tocilizumab or siltuximab ± corticosteroids and supportive care, as indicated 
for hypotension.
Grade 3: 
-Hypotension 
managed with 
1 pressor 
-Hypoxia 
requiring 
40% O2
- 
Vigilant supportive care. 
- 
Permanently discontinue study drugs(s) treatment. 
- 
Patient should be hospitalized for a minimum of a 24-hour observation period. 
 
Hypoxia:  
- 
Supplemental oxygen including high-flow oxygen delivery and non-invasive positive 
pressure ventilation. 
- 
Tocilizumab or siltuximab ± corticosteroids and supportive care, as described above. 
Hypotension: 
- 
IV fluid boluses as needed, as recommended for the treatment of Grade 2 CRS.  
- 
Tocilizumab and siltuximab as recommended for Grade 2 CRS, if not administered 
previously. 
- 
Vasopressors as needed. 
- 
Consider transfer to ICU, obtain echocardiogram, and perform hemodynamic monitoring 
as in the management of Grade 2 CRS. 
- 
Dexamethasone 10 mg IV every 6 hours; if refractory, increase to 20 mg IV every 
6 hours. 
-
Manage fever and constitutional symptoms as indicated for Grade 1 CRS.
 
 


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Table 17: Management of CRS per NCI CTCAE Version 5.0 (Continued) 
Grade 
Treatment 
Grade 3 
(Continued): 
-Hypotension 
managed with 
1 pressor 
-Hypoxia 
requiring 
40% O2
Organ toxicity: 
- 
Symptomatic management of organ toxicities, as per standard guidelines. 
-
Tocilizumab or siltuximab ± corticosteroids and supportive care, as described above.
Grade 4: 
-Life-threatening 
consequences 
-Urgent 
intervention 
indicated
- 
Vigilant supportive care. 
- 
Permanently discontinue study drug(s) treatment. 
- 
Patient should be hospitalized for a minimum of a 24-hour observation period. 
 
Hypoxia:  
- 
Mechanical ventilation. 
- 
Tocilizumab or siltuximab ± corticosteroids and supportive care, as described above. 
 
Hypotension: 
- 
IV fluids, anti-IL-6 therapy, vasopressors, and hemodynamic monitoring as defined for 
the management of Grade 3 CRS. 
- 
Methylprednisolone 1 to 2 g/day IV. 
- 
Manage fever and constitutional symptoms as indicated for Grade 1 CRS. 
 
Organ toxicity: 
- 
Symptomatic management of organ toxicities, as per standard guidelines. 
- 
Tocilizumab or siltuximab ± corticosteroids and supportive care, as described above. 
- 
In cases where neither tocilizumab, siltuximab, nor glucocorticoids are effective, other 
immunosuppressants such as the T cell-depleting antibody therapies, including 
alemtuzumab and ATG, IL1R-based inhibitors (anakinra) or cyclophosphamide might be 
of benefit. 
ATG = antithymocyte globulin; CRS = cytokine release syndrome; H2 = histamine; ICU = intensive care unit; IL = interleukin; 
IV = intravenous(ly); NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
O2 = oxygen; SBP = systolic blood pressure; T cell = thymus lymphocyte cell. 
Source: U.S. Department of Health and Human Services. National Institutes of Health. National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE). Version 5.0. 27 November 2017 
5.4.5.4 
Management of adverse events in combination arms 
AEs associated with pembrolizumab or ipilimumab exposure may represent an immunologic 
etiology. These irAEs may occur shortly after the first dose or several months after the last dose 
of pembrolizumab/ipilimumab treatment and may affect more than 1 body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab or ipilimumab, administration of corticosteroids, and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may 
be included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab/ipilimumab, and administer corticosteroids. Consultation with 
disease-specific specialists should be considered. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab and ipilimumab are provided in Table 18 and 
Table 19, respectively. 


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Attribution of toxicity and holding study drugs 
When study drugs are administered in combination, attribution of an AE to a single component is 
likely to be difficult. Therefore, while the Investigator may attribute a toxicity event to the 
combination, to ANV419 alone, to pembrolizumab alone, or to ipilimumab alone, for AEs listed 
in Table 18 and Table 19, both interventions must be held according to the criteria in Table 18 and 
Table 19. 
For AEs that occur with the combination of ANV419 and pembrolizumab or ANV419 and 
ipilimumab that clearly can be attributed to ANV419, please refer to Section 5.4.5 for management 
guidelines and recommended dose modifications to be taken for ANV419.  
For combination arms of this study, both drugs should be held until the attribution of an irAEs can 
be fully analyzed and has resolved to baseline or Grade 1. In general, Grade 3 TEAEs in the 
combination treatment arms will result in discontinuation of both ANV419 and pembrolizumab or 
ANV419 and ipilimumab, but, in rare instances, continuing either ANV419, pembrolizumab, or 
ipilimumab may be allowed where clinical benefit can be documented after resolution of toxicity 
to baseline or Grade 1. In the event that a toxicity results in holding ANV419, pembrolizumab, 
ipilimumab, or the combination of ANV419 and pembrolizumab or the combination of ANV419 
and ipilimumab for 42 days, the drugs should be permanently discontinued for that patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 18. Dose Modification for ANV419 in Combination With Pembrolizumab 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Pembrolizumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Pneumonitis 
Grade 2
Withhold. 
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper. 
Add prophylactic 
antibiotics for 
opportunistic 
infections.
Monitor 
participants for 
continuing signs 
and symptoms of 
pneumonitis. 
Evaluate 
participants with 
radiographic 
imaging.
Recurrent 
Grade 2,  
Grade 3 or 4 
Withhold study 
treatment. 
Upon 
resolution to 
Grade 1, may 
resume study 
treatment 
1 dose level 
lower.
Permanently 
discontinue.
Diarrhea/colitis 
Grade 2 or 3
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper. 
 
Monitor 
participants for 
continuing signs 
and symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation (ie, 
peritoneal signs 
and ileus). 
Participants with 
Grade 2 diarrhea 
suspected colitis 
should consider 
GI consultation 
and performing 
endoscopy to rule 
out colitis. 
Participants with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If 
sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via IV 
infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue.
Permanently 
discontinue.


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Table 18. Dose Modification for ANV419 in Combination With Pembrolizumab 
(Continued) 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Pembrolizumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
AST or ALT 
elevation or 
increased bilirubin 
Grade 20
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
0.5 to 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 30 or 40
Permanently 
discontinue.
Permanently 
discontinue.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper.
T1DM or 
hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.0
Initiate insulin 
replacement therapy 
for participants with 
T1DM. 
Administer 
antihyperglycemic 
in participants with 
hyperglycemia. 
Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency). 
Grade 3 or 4
Withhold or 
permanently 
discontinue.0
Withhold or 
permanently 
discontinue.0
Hyperthyroidism 
Grade 2
Continue.
Continue.
Treat with 
nonselective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate.
Monitor for signs 
and symptoms of 
thyroid disorders. 
Grade 3 or 4
Withhold or 
permanently 
discontinue.0
Withhold or 
permanently 
discontinue.0
Hypothyroidism 
Grade 2, 3 or 4
Continue.
Continue.
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
Standard of Care.
Monitor for signs 
and symptoms of 
thyroid disorders. 
 
 
 
 
 
 


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Table 18. Dose Modification for ANV419 in Combination With Pembrolizumab 
(Continued) 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Pembrolizumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by taper. 
Monitor changes 
of renal function. 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Neurological 
toxicities 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes. 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Myocarditis 
Grade 2, 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes.
Exfoliative 
dermatologic 
conditions 
Suspected SJS, 
TEN, or DRESS
Withhold.
Withhold.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes.
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue.
Permanently 
discontinue.
All other irAEs 
Persistent 
Grade 2
Withhold.  
Upon 
Withhold. 
Upon resolution to 
Based on severity of 
AE, administer 
Ensure adequate 
evaluation to 


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resolution to 
Grade 1, may 
resume study 
treatment.
Grade 1, may 
resume study 
treatment. 
corticosteroids. 
confirm etiology 
or exclude other 
causes. 
Grade 3
Withhold or 
discontinue 
based on the 
event.0
Withhold or 
discontinue based 
on the event.0
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue.
Permanently 
discontinue.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 18. Dose Modification for ANV419 in Combination With Pembrolizumab 
(Continued) 
Note: Non-irAEs will be managed as appropriate, following clinical practice recommendations. 
AST/ALT = 3 to 5 × ULN if baseline is normal; 3 to 5 × baseline, if baseline is abnormal; bilirubin: 1.5 to 3 × ULN if 
baseline is normal; 1.5 to 3 × baseline if baseline is abnormal. 
AST/ALT: 5 to 20 × ULN if baseline is normal; 5 to 20 × baseline, if baseline is abnormal; bilirubin: 3 to 10 × ULN if 
baseline is normal; 3 to 10 × baseline if baseline is abnormal. 
AST/ALT: 20 × ULN if baseline is normal; 20 × baseline, if baseline is abnormal; bilirubin: 10 × ULN if baseline is normal; 
10 × baseline if baseline is abnormal. 
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the Investigator or treating physician. 
If control is achieved or resolution to Grade 2, pembrolizumab may be resumed. 
Events that require discontinuation include, but are not limited to, encephalitis and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis). 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS = drug reaction with 
eosinophilia and systemic symptoms; GI = gastrointestinal; irAE = immune-related adverse event; IV = intravenous(ly); NCI 
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; SJS = Stevens-Johnson syndrome; 
T1DM = type 1 diabetes mellitus; TEN = toxic epidermal necrolysis; ULN = upper limit of normal.  
Source: Keytruda. Package Insert. Merck Sharp & Dohme Corp; 2014
 
Table 19. Dose Modification for ANV419 in Combination With Ipilimumab 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Ipilimumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Pneumonitis 
Grade 2
Withhold. 
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper. 
Add prophylactic 
antibiotics for 
opportunistic 
infections. 
Monitor 
participants for 
continuing signs 
and symptoms of 
pneumonitis. 
Evaluate 
participants with 
radiographic 
imaging. 
Recurrent 
Grade 2,  
Grade 3 or 4 
Withhold 
study 
treatment. 
Upon 
resolution to 
≤Grade 1, may 
resume study 
treatment 
1 dose level 
lower.
Permanently 
discontinue.
 


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Table 19. Dose Modification for ANV419 in Combination With Ipilimumab (Continued) 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Ipilimumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Diarrhea/colitis 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper. 
 
Monitor 
participants for 
continuing signs 
and symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) 
and of bowel 
perforation (ie, 
peritoneal signs 
and ileus). 
Participants with 
Grade 2 diarrhea 
suspected colitis 
should consider 
GI consultation 
and performing 
endoscopy to rule 
out colitis. 
Participants with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If 
sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via IV 
infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue.
Permanently 
discontinue.
AST or ALT 
elevation or 
increased bilirubin 
AST/ALT 3 to 5 
× ULN or total 
bilirubin is more 
than 1.5 × and up 
to 3 × ULN
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(initial dose of 
0.5 to 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).
 
AST/ALT 
5 × ULN or total 
bilirubin is more 
than 3 × ULN
Permanently 
discontinue.
Permanently 
discontinue.
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper.
 
 


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Table 19. Dose Modification for ANV419 in Combination With Ipilimumab (Continued) 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Ipilimumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Endocrinopathies 
Grade 2, 3, or 4
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold if not 
clinically stable.
Treatment with 
replacement or 
interventions as 
appropriate. 
Monitor for signs 
and symptoms of 
endocrinopathies. 
Hypophysitis1 
Grade 2, 3, or 4
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Resume when 
acute symptoms 
have resolved.
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency). 
Nephritis: 
with renal 
dysfunction 
Grade 2 or 3 
increased blood 
creatinine
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by taper. 
Monitor changes 
of renal function. 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Neurological 
toxicities2 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes. 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Myocarditis 
Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold.  
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes. 
 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
Exfoliative or 
bullous 
dermatologic 
conditions 
Grade 2
Withhold until 
specialist 
assessment.
Withhold until 
specialist 
assessment.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes. 
Grade 3 or 4
Permanently 
discontinue.
Permanently 
discontinue.
 


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Table 19. Dose Modification for ANV419 in Combination With Ipilimumab (Continued) 
irAEs
Grade  
(NCI CTCAE 
Version 5.0)
Action with 
ANV419
Action with 
Ipilimumab
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-Up
Ophthalmologic 
Grade 2, 3, or 4 
that does not 
improve to 
Grade 1 within 2 
weeks while 
receiving topical 
therapy or that 
requires treatment
Withhold or 
discontinue 
based on the 
event.
Permanently 
discontinue.
Based on 
recommendation by 
ophthalmologist. 
Ensure evaluation 
by 
ophthalmologist 
and continue to 
follow up as 
clinical indicated. 
All other irAEs 
Persistent Grade 2
Withhold.  
Upon 
resolution to 
Grade 1, may 
resume study 
treatment.
Withhold. 
Upon resolution to 
Grade 1, may 
resume study 
treatment.
Based on severity of 
AE, administer 
corticosteroids. 
Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes. 
Grade 3
Withhold or 
discontinue 
based on the 
event.
Withhold or 
discontinue based 
on the event.
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue.
Permanently 
discontinue.
Note: Non-irAEs will be managed as appropriate, following clinical practice recommendations. 
1. 
Signs of mass effect, including headache, photophobia, or visual field cuts. 
2. 
Permanently discontinue ipilimumab if signs of encephalitis or respiratory insufficiency due to neurological toxicity 
regardless of grade. 
AE = adverse 
event; 
ALT = alanine 
aminotransferase; 
AST = aspartate 
aminotransferase; 
GI = gastrointestinal; 
irAE = immune-related adverse event; IV = intravenous(ly); NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; ULN = upper limit of normal.  
Source: Yervoy. Package Insert. Bristol-Myers Squibb Company; 2011
5.4.5.5 
Management of infusion-related reactions for combination therapy arms 
Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. For Grade 2 
IRRs, interrupt or slow the rate of infusion.32 For Grade 3 IRRs, stop infusion and permanently 
discontinue pembrolizumab.32 
Ipilimumab 
Severe infusion reactions can occur with ipilimumab. For Grade 2 IRRs, interrupt or slow the 
rate of infusion.33 For Grade 3 IRRs, stop infusion and permanently discontinue ipilimumab.33 
5.4.6 
Treatment Compliance 
The Investigator or other study site personnel under the direction of the Investigator will be 
responsible for study drug administration and recording dosing information in source documents. 
Patient compliance will be assessed by the site using drug dispensing and infusion logs, and 
progress notes about dose reductions/interruptions. The CRF will capture infusion details and 
reasons for changes in dose level (eg, a new record completed each time dose level changes, 
including periods where no dose was taken, and the reason for a dose level change). 


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5.4.7 
Storage and Accountability 
ANV419 will be sent at -20°C under a temperature-controlled shipment and stored in a secure, 
limited access storage area at -20°C (±5°C) until use. The assigned personnel should ensure that 
the study drug is stored in accordance with the environmental conditions (temperature, light, 
humidity) as determined by the Sponsor. If concerns regarding the quality or appearance of the 
study drug arise, the study drug should not be dispensed and the Sponsor or designee should be 
contacted immediately.  
For details regarding the storage of pembrolizumab and ipilimumab, please see the approved 
package insert of each.  
Records will be maintained indicating the receipt and dispensation of all study drug supplies. At 
the conclusion of the study, the clinical site will be responsible for final drug accountability and 
destruction. 
5.5 
Prior and Concomitant Medications and/or Procedures 
5.5.1 
Excluded Medications and/or Procedures 
The following medications and procedures are prohibited during the Screening and study: 
 Any investigational agent (including investigational device) other than ANV419, 
pembrolizumab, and ipilimumab; 
 Antineoplastic systemic chemotherapy or biological therapy; 
 Immunotherapy not specified in this Protocol; 
 Radiation therapy; 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed after 
discussion between the Investigator and Sponsor. 
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology; 
Note: The use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor. 
 Live vaccines administered within 30 days of planned start of study drug; and 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
permitted; however, intranasal influenza vaccines (eg, Flu-Mist) are live attenuated vaccines 
and are prohibited. 
 Local surgery resulting from disease progression is prohibited; however, if indicated for 
palliative measure and after Investigator approval, local surgery may be permitted after the 
 12 tumor assessment. Patients who, in the opinion of the Investigator, require the use of 
any aforementioned treatments for clinical management should be removed from the study. 
5.5.2 
Allowed Medications and/or Procedures 
All treatments that the Investigator considers necessary for a patient’s welfare may be administered 
at the discretion of the Investigator in keeping with the community standards of medical care. 


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Drug-drug interaction studies have not been conducted with ANV419; however, ANV419 may 
cause the release of cytokines that may suppress CYP450 enzymes. If a patient is using any 
concomitant medications known to be sensitive substrates of CYP450 in this study, safety events 
should be closely monitored. See Appendix E for examples of sensitive clinical substrates for 
CYP450-mediated metabolism. 
5.5.3 
Documentation of Prior and Concomitant Medication Use 
The use of prior or concomitant medications will be recorded from 28 days prior to Cycle 1 Day 1 
to the Safety Follow-Up Visit up to 90 days after last dose of study drug or the start date of a new 
cancer regimen, whichever is shorter, except for concomitant medications related to cancer 
treatment, for which lifetime history prior to entering the study will be recorded. 
 
 


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6 
STUDY PROCEDURES 
All study procedures will follow the Schedule of Procedures, see Appendix A . 
 
6.1 
Tumor Measurements 
Tumor measurements will be performed as indicated in Appendix A .  
Tumors will be assessed based on RECIST (see Appendix C) and iRECIST (see Appendix D).  
Baseline disease assessment will include radiographic tumor measurements using CT imaging of 
the chest, abdomen, pelvis, or any other areas with suspected disease involvement and CT or 
magnetic resonance imaging of the brain during Screening.  
On-study scans should be performed 
 6 weeks (±7 days) from baseline until Cycle 13 (for 
 monotherapy arm) or every 9 weeks (±7 days) from baseline until Cycle 7 (for combination 
 arms), using the same modality as used for baseline imaging until progressive disease per 
RECIST and iRECIST, withdrawal of consent, or initiation of a new anticancer therapy. Brain 
imaging is only to be repeated for patients with history, ongoing, or suspicion of central nervous 
system involvement. 
 Cycle 13 (for the monotherapy arms) or Cycle 7 (for the combination therapy arms), scans 
 be performed every 12 weeks (±7 days) from the previous assessment. 
6.2 
Eastern Cooperative Oncology Group Performance Status 
ECOG Performance Status will be assessed as indicated in Appendix A using the ECOG scale 
(see Appendix G). 
6.3 
Quality of Life Evaluation 
Quality of Life (QoL) evaluations (EQ-5D-5L and QLQ-C30) are to be performed for clinical 
benefit assessment at baseline and every 12 weeks after Cycle 1 Day 1 in combination arms 
(Arms B and C). 
6.4 
Optional Tissue Biopsies 
For patients consenting to biopsy, fresh tumor tissue will be collected at screening and then on-
study within ±3 days of the imaging assessment and 7 days of the start of the next dosing cycle. 
Biopsy will be performed if the procedure is considered at low risk for the patient, clinically 
feasible and if the tumor is of sufficient size to be biopsied, otherwise, for baseline specimens, 
archived biopsy might be used if not older than 3 months at time of ICF signature. Any tissue that 
is suspected to contain tumor, including lymph nodes, may be biopsied.  
Available archived biopsies will be collected in patients who do not consent to on study biopsy, 
provided the tumor tissue is not older than 3 months at time of ICF signature.   
6.5 
Pharmacokinetic Analyses 
Serum samples for PK will be drawn as indicated in Appendix A.  
If warranted for additional safety assessments, additional samples can be collected by the 
Investigator after discussion with the Sponsor. All samples will be sent to the central laboratory. 
Please refer to the laboratory manual for details.  


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PK parameters to be analyzed: 
 Systemic clearance (CL) of ANV419; 
 Volume of distribution at steady state (Vss) of ANV419;  
 Area under the concentration-time curve (AUC) of ANV419; and 
 Maximum observed serum concentration (Cmax) of ANV419. 
6.6 
Pharmacodynamic Analyses (Immuno-Profiling and Ki67 Analysis) 
Blood samples for PD will be drawn as indicated in Appendix A.  
All samples will be sent to the central laboratory. Please refer to the laboratory manual for details. 
Immunophenotyping using flow cytometry has become the method of choice in identifying cells 
within blood samples and can therefore be used to monitor the mode of action of ANV419 as 
monotherapy or in combination with other treatments. Potential predictive markers of efficacy will 
also be explored.  
Immunophenotyping markers may include, but will not be limited to, CD3, CD4, CD8, CD25, 
FoxP3, CD56, CD16, CD279, CD366, and Ki67. 
6.7 
Exploratory Serum Biomarker Analyses 
Serum samples for biomarkers will be drawn as indicated in Appendix A. 
If warranted for an additional PD assessment or if a PD visit is missed, an additional blood sample 
can be collected by the Investigator at a later visit after discussion with the Sponsor. All samples 
will be sent to the central laboratory. Please refer to the laboratory manual for details. 
6.8 
Peripheral Blood Mononuclear Cell and Cytokine Production Analyses 
PBMC samples will be collected for all patients in the Monotherapy Dose Expansion part and 
Combination Dose Finding part. Samples will be drawn as indicated in Appendix A. 
All samples will be sent to the central laboratory. Please refer to the laboratory manual for details. 
The analysis of cytokines derived from peripheral blood stimulated immune cells will provide 
direct evidence about their functionality and potential for cytotoxic cell killing and ultimately 
reduction of tumor growth. The following markers will be analyzed in PBMC samples using flow 
cytometry or using the Isoplexis system, potentially after magnetic isolation of different cell 
populations and stimulation: cytokines including, but not limited to, Interferon γ, Tumor Necrosis 
Factor, IL-6, IL-2, and IL-10. 
6.9 
Tumor Mutational Burden and Circulating Tumor DNA Analyses 
Sampling for circulating tumor DNA (ctDNA) analyses will occur for patients that agree to 
perform tumor biopsies at the timepoints indicated in Appendix A. 
All samples will be sent to the central laboratory. Please refer to the laboratory manual for details. 
In recent years, the analysis of tumor mutational burden was shown to correlate with higher 
immunogenicity of tumors, and a correlation with response to checkpoint inhibitor treatment has 
been proposed. ctDNA has been recently described as a predictive biomarker for pembrolizumab 
as a single agent in 25 different cancers and has been shown to identify patients with highly 
favorable survival.39 Therefore, tumor mutational burden may be monitored through defined 


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commercial panels or through whole exome sequencing, and ctDNA in the blood may be analyzed 
for specific mutations defined in tumor biopsies. 
6.10 
Other Exploratory Biomarkers 
Other potential exploratory biomarkers that may be measured include the following: 
 Density and/or percentage of cell populations determined by immunohistochemistry (examples 
may include, but are not limited to, CD8, CD366 (TIM-3), CD19, CD45, Ki67, CD56, 
Immunoglobulin G1, FoxP3, CD3, CD127, CD25, CD279 (PD-1), CD4, NKG2D, CD16, 
Perforin, CD20, and tumor specific markers); 
 Concentration of peripheral blood soluble biomarkers (examples include, but are not limited 
to, soluble CD25, soluble PD-1/PD-L1, and IL-6); 
 Protein and RNA expression patterns in target cell populations and tissues outlined above 
using, but not limited to, CyTOF and/or gene expression methods; 
 Single nucleotide polymorphisms; 
 T cell receptor repertoire; 
 Epigenetic markers; and 
 Isolated immune cells from patient PBMCs analyzed via functional assays. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or to not perform or 
discontinue an analysis due to either practical or strategic reasons (eg, inadequate sample number, 
issues related to the quality of the sample, issues related to the assay that preclude analysis, or 
impossibility to perform correlative analyses, etc). Therefore, depending on the results obtained 
during the study, sample collection and/or analysis may be omitted at the discretion of Sponsor. 
6.11 
Immunogenicity Analyses 
Blood samples for anti-drug antibodies (ADA) will be drawn as indicated in Appendix A and 
analyzed at a central laboratory. Please refer to the laboratory manual for details. Additional 
samples will be taken in the case of an IRR or irAE to rule out involvement of ADA. ADA samples 
will be analyzed for anti-ANV419 antibodies, their cross-reactivity to human IL-2, and their 
capacity to neutralize ANV419 function in a cell-based assay. In case of a Grade 3 or higher IRR, 
irAE, or any other AE deemed clinically suspicious of an irAE as judged relevant by the SRC, all 
available ADA samples from the respective patient will be analyzed immediately.  
The probability of inducing a clinically relevant anti-ANV419 immune response is considered to 
be moderate. The most important potential risk associated with an anti-ANV419 humoral immune 
response is neutralization of endogenous IL-2, as this might result in systemic activation of 
immune effector cells. However, no such response was observed to aldesleukin, and therefore, this 
risk for severe consequences is considered low. In conclusion, the overall immunogenicity risk in 
the context of oncology indications is considered low to moderate as the probability of an ADA 
response is moderate while the severity of possible consequences is considered to be low.  


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6.12 
Serology 
Serology assessments will be performed as indicated in Appendix A and will include the analytes 
presented in Appendix B. 
 
6.13 
Sample Labeling and Storage 
Details regarding sample collection, preparation, handling, storage, and shipping instructions are 
provided in the Laboratory Manual. 
6.13.1 
Sample Labeling 
Each sample will be clearly labeled with the following information:  
 Protocol number; 
 Subject ID; 
 Visit; 
 Sample name; 
 Sampling time; and  
 Scheduled sampling time point. 
6.13.2 
Sample Storage 
Procedures for storage and shipment will be followed according to the Laboratory Manual. The 
samples can be destroyed by specific authorization from the Sponsor. 


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7 
SAFETY ASSESSMENTS 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All Aes, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
Aes, which include clinical laboratory test variables, will be monitored and documented in 
accordance with NCI CTCAE version 5.0 from signing of informed consent until the Safety 
Follow-Up Visit up to 90 days after the last dose of study drug or the start of a new cancer regimen, 
whichever is shorter. Patients should be instructed to report any AE that they experience to the 
Investigator, whether or not they think the event is due to study drug. Beginning at signing of 
informed consent, Investigators should make an assessment for Aes at each visit and record the 
event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
A complete medical history will be compiled for each patient. Any medical condition already 
present at Screening should be recorded as medical history and not be reported as an AE unless 
the medical condition or signs or symptoms present at baseline changes in severity, frequency, or 
seriousness at any time during the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination (eg, electrocardiogram [ECG]) 
findings that are detected during the study or are present at the signing of informed consent and 
significantly worsen during the study should be reported as Aes, as described below. The 
Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant. Abnormal test results 
that are determined to be an error should not be reported as an AE. Laboratory abnormalities or 
other abnormal clinical findings (eg, ECG abnormalities) should be reported as an AE if any of 
the following are applicable: 
 If an intervention is required as a result of the abnormality; 
 If action taken with the study drug is required as a result of the abnormality; or 
 Based on the clinical judgment of the Investigator. 


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7.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the 
relationship cannot be ruled out. 
7.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For ANV419, pembrolizumab, 
and ipilimumab, the reference safety information is included in Section 6 of the Investigator’s 
Brochure currently in force. The reference safety information for ANV419 will be reviewed yearly 
and the periodicity of the review will be harmonized with the reporting period of the Development 
Safety Update Report where possible. 
7.1.3 
Assessment of Adverse Events by the Investigator 
The severity of all Aes should be graded according to the NCI CTCAE version 5.0. For those AE 
terms not listed in the CTCAE, the following grading system should be used: 
 CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
 CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
 CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living; 
 CTCAE Grade 4: Life threatening consequences; urgent intervention indicated; and 
 CTCAE Grade 5: Death related to the AE. 
Causality assessment 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc) is suspected; and 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
 Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
 Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
 The pharmacology and pharmacokinetics of the study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
7.1.4 
Adverse Events of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence for pre-defined (per 
the results of the ongoing Phase 1 ANV419-001 study) Aes of special interest (AESIs) throughout 
the patient’s participation in this study.  
The Investigator will assess and record any additional information on the AESI in detail on an AE 
form which must be submitted within 24 hours of awareness of the event. 
For this study, AESIs include the following: 
 Grade 3 and Grade 4 CRS; 
 Grade 3 and Grade 4 IRR;  
 Grade 3 and Grade 4 capillary leak syndrome; and 
 
Grade 3 and Grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS) as per 
the American Society for Transplantation and Cellular Therapy and National Comprehensive 
Cancer Network guidelines for ICANS.34,38 
During the course of the study, additional AESIs may be identified by the Sponsor. 
AESIs must be recorded in the eCRF. 


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7.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from Baseline Visit. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as Aes 
and assessed for seriousness. Admission to the hospital for social or situational reasons (ie, no 
place to stay, live too far away to come for hospital visits, respite care) will not be considered 
inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; or 
 An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
Note: Events of progression of a patient’s underlying cancer, as well as, events clearly related to 
the progression of a patient’s cancer (signs/symptoms of progression) should not be reported as an 
SAE unless the outcome is fatal during the study or within the safety reporting period. If the event 
has a fatal outcome during that timeframe, the event of Progression of “Type of Cancer” must be 
recorded as an SAE with NCI CTCAE Grade 5 (fatal) outcome indicated. Diagnosis of progression 
of disease or hospitalization due to signs and symptoms of disease progression alone should not 
be reported as an SAE. 
7.3 
Serious Adverse Event Reporting – Procedures for Investigators 
Initial reports 
All SAEs occurring from signing of informed consent until the Safety Follow-Up Visit up to 
90 days after the last dose of study drug, or the start of a new cancer regimen, whichever is shorter, 
must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence. 


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After the reporting window, any SAE that the Investigator considers related to study drug must be 
reported to the Medpace Clinical Safety or the Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to Medpace (contact 
information listed in Section 7.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 
Follow-up reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies or is considered lost to follow-up. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (eg, 
patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. If it is 
not possible to access the EDC system, refer to the procedures outlined above for initial reporting 
of SAEs. 
7.4 
Pregnancy Reporting 
If a patient becomes pregnant after the start of study drug or within6 months after the last dose of 
study drug, the Investigator is to stop dosing with study drug(s) immediately if applicable and the 
patient should be withdrawn from the study. End of Study procedures should be implemented at 
that time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to Medpace 
Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or6 months after the last dose of study drug, the Investigator should notify Medpace Clinical Safety 
as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible, and 
until 8 weeks after delivery to assess for congenital defects. Once the outcome of the pregnancy is 
known, the EIU form should be completed and faxed/emailed to Medpace Clinical Safety. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for reporting an SAE. 
7.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the FDA, 
applicable competent authorities in all the Member States concerned, and to the Central Ethics 
Committee, and in any case no later than 7 days after knowledge by the Sponsor/designee of such 


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a case. Relevant follow-up information will subsequently be communicated within an additional 
8 days.  
All other SUSARs will be reported to the FDA, applicable competent authorities concerned and to 
the Central Ethics Committee concerned as soon as possible but within a maximum of 15 days of 
first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal product. 
Expedited reporting of SUSARs related to all investigational medical products (IMPs), (ie, 
ANV419, pembrolizumab, and ipilimumab) is required. Expedited reporting of SUSARs, related 
to non-IMPs (NIMPs) is not required. Listings of cases related to NIMPs will be included in the 
Development Safety Update Report. 
7.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the Protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the patient has taken additional dose(s) or the Investigator has reason to suspect that 
the patient has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used not in a way that is not in accordance with the Protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of patients missing doses of 
investigational product are not considered reportable as medication error. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All Aes associated with these Special Situation reports should 
be reported as Aes or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 


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Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 
Safety Contact Information: Medpace Clinical Safety 
 SAE reporting line – USA: 
 
 medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line – Europe: 
 medpace-safetynotification@medpace.com 
7.7 
Clinical Laboratory Assessments 
Clinical laboratory assessments (urinalysis, coagulation, chemistry, serology, endocrinology, and 
hematology) will be performed locally as indicated in Appendix A and will include the laboratory 
analytes presented in Appendix B. Patients found to have treatment-emergent laboratory toxicity 
of Grades 3 or 4 will be monitored at least weekly until resolution. Urinalysis may be done by 
dipstick or microscopy. 
If applicable for logistical reason, clinical laboratory assessments can be performed within 24 
hours from ANV419 administration. 
7.8 
Vital Signs 
Vital signs will be measured as indicated in the Appendix A and will include measurements of 
systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature.  
7.9 
Electrocardiograms 
Electrocardiograms will be performed as indicated in Appendix A. Twelve-lead ECGs will be 
performed locally and should be collected in triplicate, separated by approximately 5 minutes. 
When ECG measurements coincide with blood sample draws for PK, PD, or ADA sampling, the 
ECG measurement should be timed sufficiently prior to blood sample collection without impacting 
the sample collection time. Additional triplicate ECGs may be performed as clinically indicated. 
The patient should be relaxed and in a recumbent or semi-recumbent position at least 5 minutes 
before recording an ECG. ECGs will be reviewed locally by the site and parameters will be entered 
into the EDC. 
7.10 
Physical Examinations 
Physical examinations will be performed as indicated in Appendix A.  
A full physical examination and review of relevant systems, including height, will occur at the 
 Visit, Cycle 1 Day 1, Cycle 2 Day 1, and at the End of Study Visit. Height will be 
measured at baseline only. Symptom-directed physical examination measurements are to be 
performed at all other visits and as clinically indicated. 


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8 
STATISTICS 
A Statistical Analysis Plan (SAP) will be prepared as a separate document. The SAP will include 
a more technical and detailed description of the planned statistical summaries and will be finalized 
prior to any interim analysis. 
8.1 
Analysis Populations 
The Safety Population will consist of all patients who receive at least 1 dose (or partial dose) of 
study drug(s). The Safety Population will be used for safety analyses including DLT assessments.  
The Efficacy Population will consist of all patients who receive at least 1 dose of study drug, have 
at least 1 post-baseline tumor assessment, and who are part of the Monotherapy Dose Expansion 
part, Combination Dose Finding part, or the Combination Dose Expansion part. The Efficacy 
Population will be used for efficacy analyses.  
The PK Population will consist of all patients who receive at least 1 dose of study drug and have 
at least 1 measured concentration for at least 1 of the analytes. The PK Population will be used for 
PK analyses. 
The PD Population will consist of all patients who receive at least 1 dose of study drug and have 
at least 1 evaluable pharmacodynamic sample. The PD Population will be used for PD endpoint 
analyses. 
8.2 
Statistical Methods 
8.2.1 
Sample Size Determination 
Monotherapy Dose Expansion part  
This part of the study will use Bayesian sequential monitoring. A maximum of 15 patients will be 
enrolled and treated at each dose level arm. A1and A2 monotherapy arms will be analyzed as 
independent experiments, and also overall, and the following assumptions are made: 
 Nothing is known a priori: assume a uniform prior, ie, the true ORR could be any value 
between 0% and 100%; 
 A true ORR 6% indicates treatment failure; and 
 A true ORR 10% indicates treatment success. 
With a maximum of 15 patients in an arm, if no responses were observed, then the estimated true 
ORR would be 5.9%, with 90% confidence interval (CI) (0.3%, 17.1%). This would be sufficient 
evidence to suggest that the treatment is unlikely to be successful. With a maximum of 30 patients 
overall, if no responses were observed, then the estimated true ORR would be 3.1%, with 90% CI 
(0.2%, 9.2%). This would be sufficient evidence to suggest that the treatment at either dose is 
unlikely to be successful. 
There is 95% certainty that the true ORR is greater than 10% if any 1 of the following are observed: 
 2 responses in 3 to 7 patients;  
 3 responses in 8 to 13 patients;  
 4 responses in 14 to 19 patients; or  


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 5 responses in 20 to 27 patients. 
Combination Dose Finding part 
The Combination Dose Finding part will employ BOIN29 to find the MTD/RP2D of Arm B 
(ANV419 in combination with pembrolizumab) and Arm C (ANV419 in combination with 
ipilimumab). For each arm, the following assumptions have been predefined for the dose 
escalation: 
 Target DLT rate of 25%; 
 Maximum of 25 patients; 
 Maximum of 9 patients treated at the same dose level; and  
 Maximum of 5 dose levels defined in Table 5 to be tested. 
Patients will be enrolled and treated in cohorts of 3 patients (at least). Up to 50 patients in total 
will be enrolled for the Combination Dose Finding part, with a minimum of 6 patients treated at 
RP2D. 
Combination Dose Expansion part (efficacy analysis) 
The sample size calculation is based on a Simon’s 2-stage40 design and ensures that under all 
possible distributions of patients to the 2 treatment arms, there is at least 80% power to correctly 
detect an ORR 40% and at most a Type I error rate of 10% of rejecting a null hypothesis that 
ORR 20%. This results in a sample size of 12 patients randomized to each treatment arm in 
Stage 1, followed by 13 additional patients randomized during Stage 2: a total of 25 patients per 
arm at the end of Stage 2. 
8.2.2 
Baseline Characteristics 
Demographics (ie, date of birth, race, ethnicity, and sex of the patient as allowed per local 
guidelines), and patients’ baseline clinical characteristics will be summarized for each arm by dose 
level in the Combination Dose Finding part of the study and by treatment arm in the Monotherapy 
Dose Expansion part and Combination Dose Expansion part and overall using descriptive 
statistics. 
8.2.3 
Interim Efficacy Analysis 
In Arm B or C, an interim analysis of the primary outcome will be performed at the end of Stage 1 
of the Combination Dose Expansion part of the study (once 12 evaluable patients have completed 
at least 1 disease evaluation or have discontinued from the study). Any treatment arm with an ORR 
20% per RECIST (ie, treatment arms with no more than 2 complete or partial responses) will be 
discontinued. 
8.2.4 
Final Analysis of Efficacy 
Efficacy analysis will be conducted using the Efficacy Population. The primary outcome (ORR 
per RECIST) will be presented together with a 95% CI for each treatment arm. Treatment arms 
with an observed ORR 95% CI with a lower limit above 20% and an upper limit above 40% will 
be considered for future study. All other outcomes measures will be summarized with the 
appropriate descriptive statistics. 


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Additional detail regarding derivation and analysis of efficacy outcomes are provided below: 
 ORR per RECIST is defined as the proportion of patients whose best overall response is CR 
or PR; 
 ORR per iRECIST is defined as the proportion of patients whose best overall response is 
immune CR (iCR) or immune PR (iPR); 
 Duration of response (DOR) per RECIST will be calculated for patients with CR or PR as the 
best overall response. DOR is defined as the number of weeks from the start of the first 
response (CR or PR) to the first date of progressive disease per RECIST, clinical progression, 
or death due to any cause. DOR will be summarized descriptively using the Kaplan-Meier 
method; 
 Immune DOR (iDOR) per iRECIST will be calculated for patients with iCR or iPR as the best 
overall response. iDOR is defined as the number of weeks from the start of the first response 
(iCR or iPR) to the first date of progressive disease per iRECIST, clinical progression, or death 
due to any cause. iDOR will be summarized descriptively using the Kaplan-Meier method;  
 Disease control rate (DCR) per RECIST is defined as the proportion of patients whose best 
overall response is CR, PR, or SD; (DCR = CR + PR + SD). DCR will be summarized 
descriptively; 
 Immune DCR (iDCR) per iRECIST defined as the proportion of patients whose best overall 
response is iCR or iPR or immune SD (iSD) per iRECIST; (iDCR = iCR + iPR + iSD). iDCR 
will be summarized descriptively; 
 PFS is defined as the time from the initiation of study treatment to the first occurrence of 
disease progression per RECIST or death from any cause, whichever occurs first. PFS will be 
summarized descriptively using the Kaplan-Meier method; 
 Immune PFS (iPFS) is defined as the time from the initiation of study treatment to the first 
occurrence of disease progression per iRECIST or death from any cause, whichever occurs 
first. iPFS will be summarized descriptively using the Kaplan-Meier method; 
 OS is defined as the time from the initiation of study treatment to death from any cause and 
will be summarized descriptively using the Kaplan-Meier method; 
 Time to response (TTR) per RECIST will be calculated for patients with CR or PR as the best 
overall response. TTR is defined as the time from first dose date to the start of the response 
(CR or PR) per RECIST. TTR will be summarized descriptively using the KaplanMeier 
method; and 
 Immune TTR (iTTR) per iRECIST will be calculated for patients with iCR or iPR as the best 
overall response. iTTR is defined as the time from first dose date to the start of the first 
response (iCR or iPR) per iRECIST. iTTR will be summarized descriptively using the Kaplan-
Meier method. 
8.2.5 
Analysis of Immunogenicity 
The impact of pre-existing, treatment-emergent, and treatment-boosted ADA on PK, safety, and 
efficacy read-outs will be evaluated by descriptive statistics and summarized in the Clinical Study 
Report. 


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8.2.6 
Analysis of Safety 
In general, all safety analyses will be descriptive and presented in tabular format with appropriate 
summary statistics for the Safety Population. 
The safety of ANV419 as monotherapy and in combination with pembrolizumab or ipilimumab 
will be assessed by monitoring Aes (including TEAEs, DLTs [Combination Dose Finding part 
only], AESIs, SAEs, irAEs, and Aes leading to discontinuation of the study), physical examination 
findings (including ECOG performance status), clinical laboratory assessments, vital signs 
measurements, and ECGs. Aes will be coded using the Medical Dictionary for Regulatory 
Activities and graded according to NCI CTCAE version 5.0. 
TEAEs will be summarized by System Organ Class and Preferred Term and further by grade 
according to NCI CTCAE version 5.0 and relationship to study drug.  
The impact of possible anti-ANV419 antibodies on safety of ANV419 will be assessed. 
8.2.7 
Analysis of Pharmacokinetics 
Plasma concentrations of ANV419 will be determined with a validated bioanalytical assay. 
Selected PK parameters will be calculated from plasma concentrations using noncompartmental 
analyses. Summary statistics will be generated by treatment arm as appropriate. 
PK parameters to be analyzed: 
 CL of ANV419; 
 Vss of ANV419;  
 AUC of ANV419; and 
 Cmax of ANV419. 
8.2.8 
Analysis of Pharmacodynamics 
The result, change, percent change, and maximum percent change in immunologic changes to 
selected serum cytokines and immune cell subsets in the blood and tumor microenvironment will 
be summarized descriptively. 
PD parameters to be analyzed (including, but not limited to): 
 CD3, CD4, CD8, CD56, CD16, CD25, FoxP3, CD279, and CD366. 
8.2.9 
Other Analysis 
Clinical benefit assessment Quality of Life evaluation will be summarized using descriptive 
statistics. 


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9 
DATA MANAGEMENT AND RECORD KEEPING 
9.1 
Data Management 
9.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data have been accounted for. 
9.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
9.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (CFR) 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
9.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (latest) for medical history and Aes; and 
 World Health Organization Drug Dictionary for prior and concomitant medications. 
9.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
9.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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9.3 
End of Study 
The end of the study (study completion) is defined as the date of the final statistical analysis. At 
this time, patients who are still receiving ANV419 and continue to demonstrate clinical benefit 
may enter a long-term extension study to continue ANV419 treatment. 
 


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10 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
10.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
10.2 
Institutional Review Board/Independent Ethics Committee 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of patients. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The 
Protocol, Investigator’s Brochure, informed consent form (ICF), advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB/IEC by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC prior to participation of patients in research studies. Prior 
to study onset, the Protocol, any Protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB/IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. 
10.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB/IEC and/or regulatory 
agencies. A copy of the signed ICF will be given to the patient. 
10.4 
Future Use of Biological Samples 
In order to be able to address future scientific questions, patients will be asked to allow 
biospecimen collection, cryopreservation, and banking. If the patient agrees, banked samples may 
be used for future exploratory biomarker research and drug development projects; eg, to identify 
patients who are more likely to benefit from a treatment or experience an AE, or to gain a 
mechanistic or genetic understanding of drug effects. 
Biobanking will only occur after informed consent has been given in accordance with local ethical 
and regulatory requirements. 


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Blood and tissue samples for future research studies will be cryopreserved and stored for patients 
who have consented. It is the responsibility of the Investigator or designee (if acceptable under 
local regulations), to obtain written informed consent from each individual who has consented to 
have his/her samples stored for future research in a contract laboratory facility under the 
responsibility of the Sponsor and its potential partners after adequate explanation of the aims, 
methods, objectives, and potential hazards. Patients must receive an explanation that they are 
completely free to refuse long-term storage of their samples for future research and may withdraw 
consent at any time and for any reason during the storage period of the specimen(s), and that refusal 
of long-term storage does not preclude participation in the study. 
Patient samples and information will be stored in a secure storage area and will be identified only 
by a coded patient identification number. Patient samples will be kept for a maximum of 5 years, 
after which the samples will be destroyed according to the standard procedures of the laboratory. 
At any time, if informed consent is withdrawn, no new data will be added to the study database. 
Data already obtained from the samples will continue to be kept and used. Patients have the right 
to request their identifiable samples be destroyed at any time and to be informed of any plans for 
new analyses on the retained samples. 
All samples will be stored at an external biobanking facility contracted by Anaveon AG. Measures 
are in place to comply with the applicable rules for the collection, cryopreservation, biobanking, 
and future use of biological samples and clinical data, including the following: 
 Sample and data usage must be in accordance with the ICF; 
 The facilities storing biological samples from clinical study participants are qualified for the 
storage of biological samples collected in clinical studies; 
 An appropriate sample and data management system is in place, including audit trails for 
clinical data and/or samples, and the ability to identify and destroy such samples according to 
the ICF; and 
 Data and/or samples may be transferred to third parties and other countries as specified in the 
ICF. 
10.5 
Patient Emergency Study Contact Card  
On enrollment in the study, the patient will receive a patient card to be carried at all times. The 
patient card will state that the patient is participating in a clinical research study, type of treatment, 
number of treatment packs received, and contact details in case of an SAE. 
10.6 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the Protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: Protocol, Investigator’s Brochure, eCRFs 
and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 


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The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and Protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
10.7 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/IEC as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
10.8 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
10.9 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
10.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 


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10.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  


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11 
STUDY ADMINISTRATIVE INFORMATION 
11.1 
Protocol Amendments 
Any amendments to the study Protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All Protocol amendments will undergo the same review and approval process as the 
original Protocol. A Protocol amendment may be implemented after it has been approved by all 
regulatory bodies, including the IRB/IEC, unless immediate implementation of the change is 
necessary for patient safety. In this case, the situation must be documented and reported to the 
IRB/IEC within 5 working days. 


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Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance 
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Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from 
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Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from 
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Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release 
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Bratman SV, Yang SYC, Iafolla MAJ, et al. Personalized circulating tumor DNA analysis 
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Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
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MacFarlane PM, Yang JC, Guleria AJ, et al: The hematologic toxicity of interleukin-2 in 
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APPENDIX A: SCHEDULE OF PROCEDURES 
Table 20 . Schedule of Procedures for Patients Enrolled in Arms A1 or A2 (Monotherapy) 
Week
-4 to -1
1
2
3
5
7
9
11
13 
14-23
 
 
24-52
 
 
 
 
 
53-
105
EOS
b
SF
U 
Vi
sitc
,d
Sur
viva
l 
FU 
(Q1
2W) 
d
Cycle
SCRa
BLa
C1
C2
C3
C4
C5
C6
C7 
C8 to 
C12
 
C13-
C26
C27-
C53 
 
 
Day e
-28 to 
-3
-3 to 
-1
D1
 
Informed consent
X
 
 
Eligibility criteria
X
X
X
 
 
Demographic 
informationf
X
X
 
 
Medical/ 
surgical  
history
X
X
 
 
Histology report 
(mutation status)
X
 
 
Vital signsg
 
Physical 
examinationj
 
Body weight (kg)
 
ECOG PS
X
 
12-lead ECGn
X
 
 Safety laboratory 
(local)o, p
X
 
Viral Serologyq
X
 
Thyroid hormonesr
X
 
Randomization
 


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Week
-4 to -1
1
2
3
5
7
9
11
13 
14-23
 
 
24-52
 
 
 
 
 
53-
105
EOS
b
SF
U 
Vi
sitc
,d
Sur
viva
l 
FU 
(Q1
2W) 
d
Cycle
SCRa
BLa
C1
C2
C3
C4
C5
C6
C7 
C8 to 
C12
 
C13-
C26
C27-
C53 
 
 
Day e
-28 to 
-3
-3 to 
-1
D1
 
 
Pregnancy testt
X
X
 
X
X
X
Xt 
Xt
Xt 
X
X
 
CT scanu
Xu
 
Disease evaluation 
(RECIST) u
 
Cytokine samplingw
 
PBMC sampling
 
PK samplingw
 
ADA samplingee
 
Biomarker sampling
 
Immune-profile 
sampling ff
 
ctDNA sampling
 
Tumor biopsyhh
X
 
ANV419 infusionii, jj
 
Post infusion 
monitoring 
(90 minutes) kk
 
Aesll
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X 
X
X 
X
X
 
Prior/ 
concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
X 
X
X
 
Survival
 
X 
a. 
If Screening assessments were performed within 72 hours of Cycle 1 Day 1 (C1D1), it can be combined with baseline visit and the assessments will only be 
done once. The baseline visit is to be conducted within 3 days from dosing unless otherwise specified.  


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b. The EOS Visit is 730 days 
after C1D1 OR 30 days since last dose of study drug. This will also be the same visit with the same assessments for 
patients who discontinue the study early. 
c. 
A SFU visit will be made 90 days since the last dose of study drug for safety purposes . 
d. Patients who discontinue for reasons listed in Section 4.4 other than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiation of a non-study cancer treatment, withdrawal of consent, or lost to follow-up. In addition, each patient, irrespective of disease progression, 
will be followed for survival by telephone (or public records when allowed as per local regulation) until death or study termination whichever occurs first. 
e. 
The visit window is ±3 days. For visits occurring on 
 no visit window apply. 
f. 
Demographics will include date of birth (month and year), race, ethnicity, and sex as allowed per local guidelines.  
g. Vital signs will include measurements of systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature.  
h. Vital signs will be collected pre-dose and then every 2 hours (±30 minutes) for the first 8 hours post end of infusion. 
i. 
Vital signs will occur approximately 24 hours (±4 hours) after end of infusion and then ad-hoc as clinically indicated. 
. 
j. 
From C12, a physical examination will occur at every other visit. 
k. A full physical examination and review of relevant systems will occur at this visit, including height. Height to be measured at baseline only.  
l. 
Symptom-directed physical examination is to be performed as clinically indicated.  
m. ECOG Performance Status will be assessed using the ECOG scale (see Appendix G). 
. 
n. Twelve-lead ECGs will be performed locally and should be collected in triplicate, separated by approximately 5 minutes. ECGs will be performed at screening, 
baseline and within 2 hours pre-dose and 1 hour post-dose on dosing days until 
o. Clinical laboratory assessments will be performed locally. Urinalysis, coagulation, chemistry, and hematology will include the laboratory analytes presented 
in Appendix B. Patients found to have treatment-emergent laboratory toxicity of Grades 3 or 4 will be monitored at least weekly until resolution.  
p. Urinalysis may be done by dipstick or microscopy. 
q. Including HBV, HCV, HIV1, and HIV2. 
r. 
Including T3, T4, and TSH. 
. 
s. 
Patients enrolled in the Monotherapy Dose Expansion part will be randomized by IRT and stratified by BRAF mutation status into Arms A1 or A2 on C1D1 
(-3 days). 
t. 
Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit and negative (urine or serum) pregnancy test within 
72 hours prior to study Day 1. If the urine test is positive or cannot be confirmed negative, a serum pregnancy test will be required and must be negative for 
the patient to be eligible. 
. 
u. Imaging performed prior to signing consent can be used for screening purposes if done within 8 weeks from signing consent. Baseline disease assessment 
using CT imaging (including brain assessment) is to be performed within 21 days of baseline. 
 
v. CT scan is not required at EOS if available within 4 weeks prior to the EOS Visit. 
w. If warranted for additional safety assessments, additional samples can be collected by the Investigator after discussion with the Sponsor. For patients who 
discontinue for reasons other than progressive disease, PK/ADA samples will be collected during post-treatment follow-up disease status until disease 
progression. 
x. To be collected pre-dose and then 2 (±30 minutes) and 4 hours (±1 hour) post end of infusion of ANV419. 
y. PK samples to be drawn pre-dose and then 15 minutes (±5 minute), 1 hour (±30 minutes), 2 hours (±30 minutes), 4 hours (±1 hour), and 8 hours (±1 hour) 
post end of infusion.  


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z. 
PK samples to be drawn 24 hours (±1 hour) post end of infusion. 
aa. PK samples to be drawn 72 hours (±1 hour) post end of infusion. 
bb. PK samples to be drawn pre-dose and then 1 hour (±30 minutes), and 2 hours (±30 minutes) post end of infusion. 
cc. Samples to be drawn pre-dose. 
dd. 
 
ee. All ADA samples to be taken pre-dose. Additional samples will be taken in the case of an IRR or irAE to rule out involvement of ADA. 
 
. 
ff. If warranted for an additional PD assessment or if a PD visit is missed, an additional blood sample can be collected by the Investigator at a later visit after 
discussion with the Sponsor. 
gg. To be drawn 
. 
hh. Tumor biopsies for research purpose may be performed within ±3 days of the imaging assessment and within 7 days of the start of the dosing cycle if deemed 
safe and clinically feasible . Any tissue that is suspected to contain tumor, including lymph nodes, may be biopsied. All biopsies are optional. 
ii. Acetaminophen 1 g may be given to the patients as pre-medication or following the ANV419 infusion and can be used every 8 hours as needed.  
jj. A treatment interval of at least 12 days is required. 
kk. Patients will be monitored for 90 minutes post end of infusion from C1 per individual site institutional standard. 
ll. Aes and SAEs should be recorded from signing of informed consent until the SFU Visit up to 90 days (±7 days) after last dose of study drug or the start date 
of the next cancer regimen, whichever occurs first. 
mm. 
 
ADA = anti-drug antibodies; AE = adverse event; BL = baseline; C = Cycle; CT = computed tomography; ctDNA = circulating tumor deoxyribonucleic acid; 
D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; irAE = immune-related adverse events; IRR = infusion-related reaction; PBMC = peripheral blood mononuclear cell; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SCR = Screening Visit; SFU = Safety Follow-Up; T3 = triiodothyronine; T4  
= thyroxine; TSH = thyroid-stimulating hormone. 
 


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Table 21. Schedule of Procedures for Patients Enrolled in Arm B and Arm C (Combination Therapy) 
Week
-4 to -1
1
2
3
4
5
7
10
13
16
19
22 
to 
34
35+ 
Q6W
EOSb
SFU 
Visitc,d
Survival 
FU 
(Q12W)d  
Cycle
SCRa
BLa
C1
C2
C3
C4
C5
C6
C7
C8 
to 
C12
C13+ 
Q2C
Day e
-28  
to 
-3
-3 
to  
-1
D1
 
 
Informed 
consent
X
 
Eligibility 
criteria
X
X
X
 
Demographic 
informationf
X
X
 
Medical/ 
surgical  
history
X
X
 
Histology 
report 
(mutation 
status)
X
 
Vital signsg
Physical 
examinationk
 
Body 
weight(kg)
 
ECOG PSn
X
12-lead ECGo
X
Safety 
laboratory 
(local)sq,r
X
 
Viral Serologys
X
Thyroid 
hormonest
X
 
Randomization
Pregnancy testv
X
CT scanx
Xx


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Week
-4 to -1
1
2
3
4
5
7
10
13
16
19
22 
to 
34
35+ 
Q6W
EOSb
SFU 
Visitc,d
Survival 
FU 
(Q12W)d  
Cycle
SCRa
BLa
C1
C2
C3
C4
C5
C6
C7
C8 
to 
C12
C13+ 
Q2C
Day e
-28  
to 
-3
-3 
to  
-1
D1
D2
D4
D8
D15
D1
D8
D1
D1
D4
D1
D1
D1
D1
 
 
Disease 
evaluation 
(RECIST)x
 
Cytokine 
samplingz
 
PBMC 
samplingbb
 
PK samplingz
ADA 
samplingii
 
Biomarker 
sampling
 
Immune-profile 
sampling kk
 
ctDNA 
sampling
 
SNP sampling 
(Arm C only)
 
Tumor 
biopsymm
X
 
QoL evaluation 
(EQ-5D-5L 
and 
QLQ-C30)nn
 
ANV419 
infusionoo,pp,qq
 
Pembrolizumab 
infusion (Arm 
B only)qq,rr
 


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Week
-4 to -1
1
2
3
4
5
7
10
13
16
19
22 
to 
34
35+ 
Q6W
EOSb
SFU 
Visitc,d
Survival 
FU 
(Q12W)d  
Cycle
SCRa
BLa
C1
C2
C3
C4
C5
C6
C7
C8 
to 
C12
C13+ 
Q2C
Day e
-28  
to 
-3
-3 
to  
-1
D1
D2
D4
D8
D15
D1
D8
D1
D1
D4
D1
D1
D1
D1
 
 
Ipilimumab 
infusion (Arm 
C only)qq,rr
 
 Post-infusion 
observation 
(23h)uu,vv
 
Post-infusion 
monitoring 
(90mn)ww
 
AEszz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xj
X
X
 
Prior/ 
concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xj
X
X
 
Survival
X 
a. 
If Screening assessments were performed within 72 hours of Cycle 1 Day 1 (C1D1) it can be combined with baseline visit and the assessments will only be 
done once. The baseline window is to be conducted within 3 days from dosing unless otherwise specified.  
b. The EOS Visit is 
after C1D1 OR 30 days since last dose of study drug. This will also be the same visit with the same assessments for 
patients who discontinue the study early. 
c. 
A SFU visit will be made 90 days since the last dose of study drug for safety purposes . 
d. Patients who discontinue for reasons listed in Section 4.4 other than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiation of a non-study cancer treatment, withdrawal of consent, or lost to follow-up. In addition, each patient, irrespective of disease progression, 
will be followed for survival by telephone (or public records when allowed as per local regulation) until death or study termination whichever occurs first. 
e. 
The visit window will be ±3 days, except for 
y 
f. 
Demographics will include date of birth (month and year), race, ethnicity, and sex as allowed per local guidelines.  
g. Vital signs will include measurements of systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature.  
h. Vital signs to be collected pre-dose and then every 2 hours (±30 minutes) for the first 8 hours post end of ANV419 infusion. 
i. 
Vital signs will occur approximately 20 hours (±3 hours) after end of infusion for Combination Dose Finding patients or approximately 24 hours (±4 hours) 
post end of infusion for Combination Dose Expansion patients, and then ad-hoc as clinically indicated. 
j. 
To occur every cycle following 
k. From 
. 


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l. 
A full physical examination and review of relevant systems will occur at this visit, including height. Height tobe measured at baseline only.  
m. Symptom-directed physical examination isto be performed as clinically indicated.  
n. ECOG Performance Status will be assessed using the ECOG scale (see Appendix G). ECOG 
o. Twelve-lead ECGs will be performed locally and should be collected in triplicate, separated by approximately 5 minutes. 
p. ECGs 
 
q. Clinical laboratory assessments will be performed locally. Urinalysis, coagulation, chemistry, and hematology will include the laboratory analytes presented 
in Appendix B. Patients found to have treatment-emergent laboratory toxicity of Grades 3 or 4 will be monitored at least weekly until resolution.  
r. 
Urinalysis may be done by dipstick or microscopy. 
s. 
Including HBV, HCV, HIV1, and HIV2. 
t. 
Including T3, T4, and TSH. From C5, thyroid hormones should be measured 
. 
u. Patients enrolled in the Combination Dose Finding part will be manually randomized to Arm B or Arm C on C1D1 (-3 days). Patients enrolled in the 
Combination Dose Expansion part will be randomized by IRT and stratified by BRAF mutation status into Arm B or Arm C on C1D1 (-3 days). 
v. Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit and negative (urine or serum) pregnancy test within 
72 hours prior to study Day 1. If the urine test is positive or cannot be confirmed negative, a serum pregnancy test will be required and must be negative for 
the patient to be eligible.  
w. To occur pre-dose every cycle from previous assessment and at EOS. 
x. Imaging performed prior to signing consent can be used for screening purposes if done within 8 weeks from signing consent. 
y. 
z. 
If warranted for additional safety assessments, additional samples can be collected by the Investigator after discussion with the Sponsor. 
aa. To be collected pre-dose and then 2 hours (±30 minutes) and 4 hours (±1 hour) post end of infusion of ANV419. 
bb. PBMC samples will be collected for all patients in the Combination Dose Finding part only (and no patients in Combination Dose Expansion part).  
cc. PK samples to be drawn pre-dose and then 15 minutes (±5 minute), 1 hour (±30 minutes), 2 hours (±30 minutes), 4 hours (±1 hour), and 8 hours (±1 hour) 
post end of infusion.  
dd. PK samples to be drawn 24 hours (±1 hour) post end of infusion. 
ee. PK samples to be drawn 72 hours (±1 hour) post end of infusion. 
ff. PK samples to be drawn pre-dose and then 1 hour (±30 minutes), and 2 hours (±30 minutes) post end of infusion.  
gg. Samples to be drawn pre-dose. 
hh. To be drawn pre-dose every 
. 
ii. All ADA samples to be taken pre-dose. Additional samples will be taken in the case of an IRR or irAE to rule out involvement of ADA. From C5, ADA 
samples to be taken 
jj. To be drawn 
from the previous assessment. To occur pre-dose on days where study drug is administered. 
kk. If warranted for an additional PD assessment or if a PD visit is missed, an additional blood sample can be collected by the Investigator at a later visit after 
discussion with the Sponsor. 
ll. To be drawn 
 
mm. 
Tumor biopsies for research purpose may be performed within ±3 days of the imaging assessment and within 7 days of the start of the dosing cycle if 
deemed safe and clinically feasible. Any tissue that is suspected to contain tumor, including lymph nodes, may be biopsied. All biopsies are optional. 


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nn. QoL evaluations (EQ-5D-5L and QLQ-C30) are to be performed for clinical benefit assessment at baseline and 
. 
oo. Acetaminophen 1 g may be given to the patients as pre-medication or following the ANV419 infusion and can be used every 8 hours as needed. 
pp. A treatment interval of 
. 
qq. Pembrolizumab or ipilimumab will be administered first. Patients can receive the ANV419 infusion approximately 30 minutes after they have received the 
entire infusion of pembrolizumab or ipilimumab. 
rr. Sites should make every effort to target infusion timing to be as close to 30 minutes (for pembrolizumab) or 90 minutes (for ipilimumab) as possible; however, 
given the variability of infusion pumps from site to site, a window of ±5 minutes is permitted. 
ss. Ipilimumab dosing will end after 
tt. Patients being treated on combination therapy with ANV419 plus ipilimumab who require discontinuation of ipilimumab due to toxicity may continue treatment 
with ANV419 after approval from the Sponsor. The reason for discontinuation must be recorded. 
uu. At the end of study drug(s) infusion in C1 and C2 (only) of the Combination Dose Finding part, all patients will undergo a 23-hour observation period. Clinical 
monitoring will be conducted per individual sites institutional standards within the framework of observation required for this Protocol, with vital signs 
monitored every 8 hours for the first 23 hours post end of ANV419 infusion. After C2, the observation will lessen to 90 minutes post end of infusion, provided 
no additional safety concerns have been identified. 
vv. Combination Dose Finding part patients only. 
ww. Patients will be monitored for 90 minutes or longer post end of ANV419 infusion from C1 per individual site institutional standard. 
xx. Combination Dose Expansion part patients only. 
yy. All patients in Combination Dose Finding part and Combination Dose Expansion part, provided no additional safety concerns have been identified. 
zz. AEs and SAEs should be recorded from signing of informed consent until the SFU Visit up to 90 days (±7 days) after last dose of study drug or the start date 
of the next cancer regimen, whichever occurs first. 
ADA = anti-drug antibodies; AE = adverse event; BL = baseline; BRAF = B-type Raf proto-oncogene; C = Cycle; CT = computed tomography; 
ctDNA = circulating tumor deoxyribonucleic acid; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; 
EQ-5D-5L= Euro-QoL 5 dimension 5 level; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; irAE = immune-related 
adverse events; IRR = infusion-related reaction; IRT = interactive response technology; PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); 
QLQ-C30 = quality of life core 30; QoL = quality of life; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; SCR = Screening Visit; SFU = Safety Follow-Up; SNP = single nucleotide polymorphism;  
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total protein 
Total and Direct bilirubin 
Urea (where blood urea nitrogen is not 
tested) 
Uric acid 
 
 
 
Additional Chemistry Parameters 
C-reactive protein 
Cholesterol 
Triglycerides 
 
 
Endocrinology 
Thyroid-stimulating hormone 
T3 
T4 
 
T3 = triiodothyronine; T4 = thyroxine. 
 
Hematology 
Absolute basophil value 
Absolute eosinophil value 
Absolute monocyte count 
Absolute neutrophil count 
Hematocrit 
Hemoglobin 
Lymphocyte count 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Coagulation 
D-dimer 
International normalized ratio [1] 
Prothrombin ratio 
Prothrombin time 
1. 
Prothrombin time/international normalized ratio should be measured daily for any patient experiencing alanine 
aminotransferase or aspartate aminotransferase elevations 3 × upper limit of normal with concomitant elevation in 
bilirubin 2 × upper limit of normal until resolution to baseline of the liver function test abnormality.


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Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Urinalysis may be done by dipstick or microscopy. 
 
Serology 
Hepatitis B surface antigen 
Hepatitis B virus DNA [1] 
Hepatitis C virus antibody 
Hepatitis C virus RNA [2] 
Human immunodeficiency virus 1 
Human immunodeficiency virus 2 
1. 
Hepatitis B virus DNA will be tested by PCR in patients with positive hepatitis B surface antigen. 
2. 
Hepatitis C virus RNA will be tested by PCR in patients with positive hepatitis C virus antibody. 
DNA = deoxyribonucleic acid; PCR = polymerase chain reaction; RNA = ribonucleic acid. 
 


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APPENDIX C: TUMOR MEASUREMENTS AND ASSESSMENT OF 
DISEASE RESPONSE USING RESPONSE EVALUABLE CRITERIA IN 
SOLID TUMORS (RECIST) 1.1 
Tumor measurements are to be performed for all patients during Screening as follows: 
 Baseline disease assessment: radiographic tumor measurements using computed tomography 
(CT) imaging of the chest, abdomen, pelvis, or any other areas with suspected disease 
involvement, and CT or magnetic resonance (MR) imaging of the brain during Screening. For 
brain imaging, MR imaging without and with contrast is preferred and CT with contrast is 
acceptable if MR imaging is medically contraindicated. For each modality, intravenous (IV) 
and oral contrast should be utilized (chest CT does not require IV contrast) where applicable 
unless medically contraindicated.  
Thereafter, tumor measurements and disease response assessments are to be performed as follows: 
Radiographic disease assessment: 
 6 weeks (±7 days) from baseline until Cycle 13(for 
 arm) or every 9 weeks (±7 days) from baseline until Cycle 7 (for combination therapy 
 using the modality as used for baseline imaging assessment until progressive disease, 
 of consent, or initiation of a new anti-cancer therapy, per Response Evaluation Criteria 
 Solid Tumors (RECIST) 1.1 and immune RECIST (iRECIST). Brain imaging is only to be 
 for patients with history, ongoing, or suspicion of central nervous system involvement. 
 Cycle 13 (for the monotherapy arm) or Cycle 7 (for the combination therapy arms), scans 
 be performed every 12 weeks (±7 days) from the previous assessment. 
Anatomical measurements (summed across target lesions) will be documented during Screening 
and each subsequent evaluation. When possible, the same qualified physician will interpret results 
to reduce variability. Test results and Investigator’s findings will be filed in the patient’s source 
documents. 
During Screening, tumor lesions are to be categorized as measurable versus nonmeasurable and 
target versus nontarget, as follows: 
Measurable versus nonmeasurable 
 Measurable: Lesions that could accurately be measured in at least 1 dimension, the longest 
diameter in the plane of measurement to be recorded as:  
o Tumor lesions: 10 mm by CT scan; 
o Malignant lymph nodes: To be considered pathologically enlarged and measurable, the 
node must be 15 mm in short axis when assessed by CT scan. At baseline and in 
follow-up, only the short axis will be measured and followed. Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.  
 Nonmeasurable: All other lesions, including small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), and truly nonmeasurable lesions. 
Target versus nontarget 
 Target: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, are to be identified as target lesions and measured and 


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recorded at Screening. Target lesions are to be selected on the basis of their size (ie, those with 
the longest diameter) and suitability for accurate repeated measurement. Lymph nodes may 
be selected as target lesions; they must be defined as measurable and only the short axis of the 
node will contribute to the baseline sum. All other pathologic nodes with short axis 10 mm 
but 15 mm should be considered nontarget lesions. 
 Nontarget: All other lesions not classified as target lesions (or sites of disease) are to be 
identified as nontarget lesions and are to be recorded in the electronic Case Report Form 
(eCRF). Measurement of nontarget lesions is not required. 
The sum of diameters (longest for non-nodal lesions and short axis for nodal lesions) for all target 
lesions is to be calculated and recorded in the eCRF as the baseline sum diameters. 
Disease response in target and nontarget lesions will be assessed by the Investigator using 
RECIST 1.1, according to the categories and criteria described in Table 22 below. The best overall 
response for each patient will be reported as the best response documented over the sequence of 
objective statuses recorded using the categories and criteria in Table 22. 
Table 22. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Guidelines for 
Tumor Response 
Disease Response Criteria for Target and Non-Target Lesions
Evaluation of target lesions
Complete response
Disappearance of all target lesions. Any pathologic 
nodes (whether target or nontarget lesions) must have a 
reduction in SAD to 10 mm.
Partial response
At least a 30% decrease in the SOD (LD for non-nodal 
lesions and SAD for nodal lesions) of target lesions, 
taking as reference the baseline sum LD.
Stable disease
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease, 
taking as reference the smallest sum LD since the 
treatment started.
Progressive disease
At least a 20% increase in the SOD of target lesions, 
taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest sum on 
study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm (Note: The appearance of 1 or more new 
lesions is also considered progression).
Evaluation of non-target lesions
Complete response
Disappearance of all nontarget lesions and 
normalization of tumor marker level.
Incomplete response/Stable disease
Persistence of 1 or more nontarget lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits.
Progressive disease
Appearance of 1 or more new lesions and/or 
unequivocal progression of existing nontarget lesions.
LD = longest diameter; PR = partial response; SAD = short axis diameters; SOD = sum of the diameters. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247
 
 
 


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APPENDIX D: MODIFIED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS 1.1 FOR IMMUNE-BASED THERAPEUTICS (IRECIST) 
QUICK REFERENCE 
The principles used to establish objective tumor response are largely unchanged from Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1, but the major change for immune-RECIST 
(iRECIST) (ie, Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics) is the concept of resetting the bar if RECIST 1.1 progression is followed at the next 
assessment by tumor shrinkage. iRECIST define immune-unconfirmed progressive disease 
(iUPD) on the basis of RECIST 1.1 principles; however, iUPD requires confirmation, which is 
done on the basis of observing either a further increase in size (or in the number of new lesions) in 
the lesion category in which progression was first identified in (ie, target or nontarget disease), or 
progression (defined by RECIST 1.1) in lesion categories that had not previously met RECIST 1.1 
progression criteria. However, if progression is not confirmed but instead tumor shrinkage occurs 
(compared with baseline), which meets the criteria of immune-complete response, immune-partial 
response, or immune-stable disease, then the bar is reset so that iUPD needs to occur again 
(compared with nadir values) and then be confirmed (by further growth) at the next assessment for 
immune-confirmed progressive disease to be assigned. If no change in tumor size or extent from 
iUPD occurs, then the time point response would again be iUPD. This approach allows atypical 
responses, such as delayed responses that occur after pseudo-progression, to be identified, further 
understood, and better characterized. 
See Table 23 for a comparison between RECIST 1.1 and iRECIST. 
Table 23 Comparison Between RECIST 1.1 and iRECIST 
 
RECIST 1.1
iRECIST
Definition of measurable and 
nonmeasurable disease; numbers 
and site of target disease
Measurable lesions are 10 mm in 
diameter (15 mm for nodal 
lesions); maximum of 5 lesions 
(2 per organ); all other disease is 
considered nontarget (must be 
10 mm in short axis for nodal 
disease).
No change from RECIST 1.1; 
however, new lesions are assessed 
as per RECIST 1.1 but are recorded 
separately on the case report form 
(but not included in the sum of 
lesions for target lesions identified 
at baseline). 
CR, PR, or SD
Cannot have met criteria for 
progression before CR, PR, or SD.
Can have had iUPD (1 or more 
instances), but not iCPD, before 
iCR, iPR, or iSD.
Confirmation of SD
Not required.
Not required.
 
 


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Table 23Table 23 
Comparison Between RECIST 1.1 and iRECIST (Continued) 
RECIST 1.1
iRECIST
New lesions
Result in progression; recorded but 
not measured.
New lesions should be assessed and 
categorized as measurable or 
nonmeasurable using RECIST 1.1. 
New lesions result in iUPD, but 
iCPD is only assigned on the basis 
of this category if at the next 
assessment, additional new lesions 
appear or an increase in size of new 
lesions is seen (5 mm for the sum 
of new lesion target or any increase 
in new lesion nontarget); the 
appearance of new lesions, when 
none have previously been 
recorded, can also confirm iCPD.
Confirmation of progression
Not required (unless equivocal).
The next imaging assessment 
should be performed at 4 weeks 
but 8 weeks after iUPD. 
Progression is confirmed if the next 
imaging assessment confirms a 
further increase in size of at least 
5 mm in the lesion category in 
which progression was first 
identified, or progression in a lesion 
category that had not previously 
met RECIST 1.1 progression 
criteria, or development of new 
lesions. However, the criteria for 
iCPD (after iUPD) are not 
considered to have been met if iCR, 
iPR, or iSD criteria (compared with 
baseline and as defined by 
RECIST 1.1) are met at the next 
assessment after iUPD. The status 
is then reset and iCR, iPR, or iSD 
should be documented.
Consideration of clinical status
Not included in assessment.
Clinical stability is considered 
when deciding whether treatment is 
continued after iUPD.
CR = complete response; iCPD = immune-confirmed progressive disease; iCR = immune-complete response; 
iPR = immune-partial response; iRECIST = immune-Response Evaluation Criteria in Solid Tumors; iSD = immune-stable 
disease; iUPD = immune-unconfirmed progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in 
Solid Tumors; SD = stable disease. 
 
 
 
 
 
 
 
 
 


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APPENDIX E: EXAMPLES OF SENSITIVE CLINICAL SUBSTRATES 
FOR P450-MEDIATED METABOLISM (FOR CONCOMITANT USE IN 
CLINICAL DDI STUDIES AND/OR LABELING) 
Table 24. Examples of Sensitive Clinical Substrates for P450-Mediated Metabolism 
Sensitive Substrates
CYP1A2
alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine
CYP2B6
bupropionaaa
CYP2C8
repaglinidebbb
CYP2C9
celecoxibccc
CYP2C19
S-mephenytoin, omeprazole
CYP2D6
atomoxetine, desipramine, dextromethorphan, eliglustat,ddd nebivolol, nortriptyline, 
perphenazine, tolterodine, R-venlafaxine
CYP3A
alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavireee, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatinfff, midazolam, naloxegol, nisoldipine, saquinavireee, 
simvastatinfff, sirolimus, tacrolimus, tipranavireee, triazolam, vardenafil
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavireee, 
lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of 5-fold with strong index inhibitors of a given 
metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with 10-fold increase in AUC by co-administration 
of strong index inhibitors are shown. Other elimination pathways may also contribute to the elimination of the substrates listed 
in the table above and should be considered when assessing the drug interaction potential. 
This table was prepared to provide examples of clinical substrates and not intended to be an exhaustive list. DDI data were 
collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database 
(Source: Hachad H, Ragueneau-Mejlessi I, Levy RH, et al. A useful tool for drug interaction evaluation: the University of 
Washington Metabolism and Transport Drug Interaction Database. Hum Genomics. 2010;5[1]:1-12). 
aaa. Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of other 
pathway(s). 
bbb. OATP1B1 substrate. 
ccc. Listed based on pharmacogenetic studies. 
ddd. Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
eee. Usually administered to patients in combination with ritonavir or cobicistat, strong CYP3A inhibitors. 
fff. Acid form is an OATP1B1 substrate. 
AUC = area under the concentration versus time curve; CYP = cytochrome P450; DDI = drug-drug interaction; 
OATP1B1 = organic anion transporting polypeptide 1B1. 
Source: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers#table3-1
 
 


Anaveon AG 
Clinical Study Protocol ANV419-101 
Confidential & Proprietary 
Page 126 of 128 
Version 4.0, 07 March 2023 
APPENDIX F: ANV419 SAFETY EVENTS 
Table 25. Study ANV419-001: Drug Related Treatment Emergent Adverse Events 
System Organ Class 
 
Preferred Term 
No Patients (%) 
N=34
 
Any TEAE related to ANV419
33 (97%)
General Disorders and 
administration site conditions  
Pyrexia
25 (74%)
Chills
21 (62%)
 
Asthenia
7 (21%)
Fatigue
6 (18%)
Malaise
3 (9%)
 
Hot flush
1 (3%)
Lethargy
1 (3%)
Oedema peripheral
1 (3%)
 
Temperature regulation disorder
1 (3%)
Gastrointestinal disorders 
Vomiting
12 (35%)
Nausea
11 (32%)
 
Diarrhea
4 (12%)
Abdominal discomfort
1 (3%)
Abdominal pain
1 (3%)
 
Abdominal pain upper
1 (3%)
Colitis
1 (3%)
Dyspepsia
1 (3%)
 
Dysphagia
1 (3%)
Flatulence
1 (3%)
Gastro-esophageal reflux disease
1 (3%)
Investigations 
 
Alanine aminotransferase 
increased
6 (18%) 
 
Aspartate aminotransferase 
increased
6 (18%) 
Blood bilirubin increased
6 (18%)
 
Blood creatinine increased
2 (6%)
 
Blood alkaline phosphatase 
increased
1 (3%) 
 
C-reactive protein increased  
1 (3%)
 
Gamma-glutamyl transferase 
increased
1 (3%) 
 
Platelet count decreased
1 (3%)
Decreased appetite
7 (21%)


Anaveon AG 
Clinical Study Protocol ANV419-101 
Confidential & Proprietary 
Page 127 of 128 
Version 4.0, 07 March 2023 
Metabolism and nutrition 
disorders 
Hyponatremia
1 (3%)
 
Dehydration
1 (3%)
Hypocalcemia
1 (3%)
Skin and subcutaneous tissue 
disorders 
Rash maculo-papular
4 (12%)
 
Pemphigoid
1 (3%)
Hyperhidrosis
1 (3%)
Rash
1 (3%)
Immune system disorders
 
Cytokine release syndrome
8 (24%)
Blood and lymphatic system 
disorders 
Lymphopenia
3 (9%)
Anemia
2 (6%)
 
Thrombocytopenia
2 (6%)
Neutropenia
1 (3%)
Musculoskeletal and 
connective tissue disorders 
 
Myalgia
4 (12%)
 
Back pain
1 (3%)
Pain in extremity
1 (3%)
Renal and urinary disorders 
Cystitis noninfective
2 (6%)
 
Dysuria
1 (3%)
Vascular disorders
Hypotension
4 (12%)
Infections and infestations
Rash pustular
2 (6%)
Nervous system disorders 
 
Hypoesthesia
1 (3%)
Peripheral sensory neuropathy
1 (3%)
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea
1 (3%)
 
Pleural effusion
1 (3%)
 


Anaveon AG 
Clinical Study Protocol ANV419-101 
Confidential & Proprietary 
Page 128 of 128 
Version 4.0, 07 March 2023 
APPENDIX G: EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Table 26. ECOG Performance Status 
Grade 
Descriptions 
0
Normal activity. Fully active, able to carry on all pre-disease performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light sedentary nature (eg, light housework, office work).
2
In bed 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed 50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
ECOG = Eastern Cooperative Oncology Group. 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982;5(6):649-655
 

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