A Phase 1b/2a, Open-Label, Multi-Center Study of CyPep-1 in Combination With Pembrolizumab to Evaluate the Efficacy and Safety of CyPep-1 in Patients With Advanced or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC), Melanoma, or Triple-Negative Breast Cancer (TNBC) (CATALYST)
Phase: PHASE1
Conditions: Advanced Head and Neck Squamous Cell Carcinoma, Advanced Breast Cancer, Advanced Melanoma
Sponsor: Cytovation AS

 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 1b/2a, Open-Label, Multi-Center Study of CyPep-1 in 
Combination With Pembrolizumab to Evaluate the Efficacy and 
Safety of CyPep-1 in Patients With Advanced or Metastatic Head 
and Neck Squamous Cell Carcinoma (HNSCC), Melanoma, or 
Triple-Negative Breast Cancer (TNBC) (CATALYST) 
 
Investigational Product: CyPep-1 and pembrolizumab 
Protocol Number: CYP003 
EudraCT Number: 2021-006804-34 
 
 
Sponsor: 
Cytovation ASA 
Solheimsgaten 11 
5058 Bergen 
Norway 
Telephone: +47 477 18 809 
 
Original Protocol: 07 January 2022 
Amendment 1 (Version 2.0): 09 March 2022 
Amendment 2 (Version 3.0): 20 May 2022 
Amendment 3 (Version 4.0): 23 November 2022 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Cytovation ASA except to the extent that disclosure would be required by law and for 
the purpose of evaluating and/or conducting a clinical study for Cytovation ASA. 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 Cytovation ASA 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 Cytovation ASA 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 Cytovation ASA 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 Cytovation ASA, 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 1b/2a, Open-Label, Multi-Center Study of CyPep-1 in Combination With 
Pembrolizumab to Evaluate the Efficacy and Safety of CyPep-1 in Patients With Advanced or 
Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC), Melanoma, or Triple-Negative 
Breast Cancer (TNBC) (CATALYST) 
PROTOCOL NUMBER:  CYP003 
INVESTIGATIONAL PRODUCT:  CyPep-1 and pembrolizumab 
PHASE:  1b/2a 
INDICATIONS:  Advanced or metastatic head and neck squamous cell carcinoma (HNSCC), 
melanoma, or triple-negative breast cancer (TNBC) 
OBJECTIVES AND ENDPOINTS: 
The study objectives and endpoints are provided in Table S1. 
Table S1. Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
Phase 1b 
Confirm the recommended CyPep-1 dose (20 mg 
Q2W) when administered by IT injection in 
combination with pembrolizumab  
 
Incidence, frequency, and seriousness of TEAEs; 
 
Incidence of DLTs; and 
 
Changes from baseline in vital signs, body weight, 
12-lead ECG parameters, and laboratory 
assessments. 
Phase 2a 
Assess the anti-tumor activity of CyPep-1 administered 
by IT injection in combination with pembrolizumab  
ORR based on radiological assessment according to 
RECIST v1.1 
Secondary Objectives 
Secondary Endpoints 
Phase 1b 
Evaluate the PK of CyPep-1 in combination with 
pembrolizumab 
 
Plasma concentration-time profile of CyPep-1 and, 
if detectable, the following derived PK 
parameters:  
o 
AUC; 
o 
Cmax; 
o 
Tmax;  
o 
CL; 
o 
t½; and 
o 
VD. 
 

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Table S1. Objectives and Endpoints (Continued) 
Secondary Objectives 
Secondary Endpoints 
Phase 2a 
Expand evaluation of efficacy CyPep-1 + 
pembrolizumab  
 
ORR according to iRECIST; 
 
DCR according to iRECIST and RECIST v1.1;  
 
DoR according to iRECIST and RECIST v1.1; 
 
PFS according to iRECIST and RECIST v1.1; and 
 
OS for up to 26 months from Cycle 1 Visit 1. 
Evaluate the safety and tolerability of CyPep-1 in 
combination with pembrolizumab 
 
Incidence, frequency, and seriousness of TEAEs; 
and 
 
Changes from baseline in vital signs, body weight, 
12-lead ECG parameters, and laboratory 
assessments. 
Exploratory Objectives 
Exploratory Endpoints 
Analyze changes in biomarkers and tumor kinetics 
associated with the mode of action of CyPep-1 and 
pembrolizumab by tumor biopsy from injected lesions 
 
Number and relative change of tumor infiltrating 
immune cells; 
 
Expression of selected immune cell biomarkers; 
 
Change from baseline in target tumor lesion size 
over time, overall, and by injected versus 
non-injected lesions; 
 
Maximum decrease from baseline in target tumor 
lesions, overall, and by injected versus 
non-injected lesions; and  
 
Changes in new lesions treated with CyPep-1. 
Expand evaluation of anti-tumor activity of CyPep-1 
and pembrolizumab 
ORR according to itRECIST 
AUC = area under the curve; CL = systemic clearance; Cmax = peak plasma concentration; DCR = Disease Control Rate; 
DLT = dose-limiting toxicity; DoR = Duration of Response; ECG = electrocardiogram; iRECIST = immune-Response 
Evaluation Criteria in Solid Tumors; IT = intra-tumoral; itRECIST = intratumoral-Response Evaluation Criteria in Solid 
Tumors; ORR = Objective Response Rate; OS = Overall Survival; PFS = Progression Free Survival; PK = pharmacokinetic(s); 
Q2W = every 2 weeks; Q6W = every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; t½ = elimination 
half-life; TEAE = treatment-emergent adverse event; Tmax = time to reach peak plasma concentration; v = version; VD = volume 
of distribution. 
 
POPULATION: 
No waivers for inclusion or exclusion criteria will be given. 
General Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Are 18 years of age or older on the day of signing informed consent; 
2. Provide written informed consent and are able to comply with study procedures and 
assessments; 
3. Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 
(v)1.1 as assessed by the local site Investigator/radiology. Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such 
lesions; 
4. Have at least 1 non-ulcerated, measurable, and accessible lesion for intra-tumoral (IT) 
injection with a maximum diameter of 5 cm; 

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5. Are able to provide tissue from a core or excisional biopsy at screening or have an acceptable 
stored tumor sample available that was collected within 90 days prior to screening;  
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 
7. Have a life expectancy 3 months, as determined by the Investigator; 
8. Female patients of non-childbearing potential must be either surgically sterile (hysterectomy, 
bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before 
screening), post-menopausal, defined as spontaneous amenorrhea for at least 2 years, or with 
follicle-stimulating hormone in the post-menopausal range at screening; 
9. Female patients of childbearing potential (defined as <2 years after last menstruation or not 
surgically sterile) must have a negative serum pregnancy test at screening and agree to use a 
highly effective method for contraception from the time of signing the informed consent form 
(ICF) until at least 120 days after the last administration of study treatment. Highly effective 
methods of contraception are birth control methods with a failure rate of <1% per year when 
used consistently and correctly, including the following: 
o Combined estrogen- and progestin-containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally; progestin-only 
hormonal contraception associated with inhibition of ovulation given orally, by injection, 
or by implant; intrauterine devices; and intrauterine hormone-releasing systems; 
o Female sterilization (surgical bilateral oophorectomy with/without hysterectomy, total 
hysterectomy, bilateral tubal occlusion/ligation) at least 26 weeks prior to first study 
treatment; 
o Sterilization of male partner (at least 6 months prior to first study treatment dose); and 
o Complete sexual abstinence. Periodic abstinence (eg, calendar) and withdrawal are not 
acceptable. 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 treatment. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the patient. 
10. Male patients able to father children must agree to use 2 acceptable methods of contraception 
throughout the study (eg, condom plus spermicidal gel). Sperm donation is not recommended 
from the time of signing the ICF until at least 120 days after the last administration of study 
treatment; and 
11. Have adequate organ function as defined in Table S2. Specimens must be collected within 
72 hours prior to the start of study treatment at Cycle 1 Visit 1. 

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Table S2. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
ANC 
1500/µL 
Platelets 
100,000/µL 
Hemoglobin1 
9.0 g/dL or 5.6 mmol/L 
Renal 
Creatinine OR 
Measured or calculated CrCl2 (GFR can also be used 
in place of creatinine or CrCl) 
1.5 × ULN OR 
30 mL/min for patients with creatinine levels 
>1.5 × institutional ULN 
Hepatic 
Total bilirubin 
1.5 × ULN OR direct bilirubin ULN for 
patients with total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
2.5 × ULN ( 5 × ULN for patients with liver 
metastases) 
This table includes eligibility-defining laboratory value requirements for treatment. 
1. 
Criteria must be met without pRBC transfusion within the prior 2 weeks. Patients can be on a stable dose of 
erythropoietin (approximately 3 months). 
2. 
CrCl should be calculated per institutional standard. 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); ANC = absolute neutrophil count; AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; 
GFR = glomerular filtration rate; pRBC = packed red blood cell; ULN = upper limit of normal. 
Inclusion Criteria for Arm A 
Patients who meet all of the general Inclusion Criteria and the following additional criteria will be 
eligible for inclusion in Arm A: 
1. Have histologically confirmed diagnosis of HNSCC (including nasopharyngeal squamous cell 
carcinoma); 
2. Have advanced or metastatic HNSCC incurable by standard of care therapies; and  
3. Have recurrent or metastatic HNSCC that has progressed on or failed both platinum-based 
chemotherapy AND an immune checkpoint inhibitor (ICI) (given either sequentially or 
concurrently). 
Note: Patients who received platinum-based chemotherapy with concurrent radiation for 
locally advanced HNSCC and experienced disease progression within 6 months may also be 
considered as having disease progression on platinum-based chemotherapy. 
Inclusion Criteria for Arm B 
Patients who meet all of the general Inclusion Criteria and the following additional criteria will be 
eligible for inclusion in Arm B: 
1. Have histologically confirmed diagnosis of malignant melanoma; 
2. Do not have uveal melanoma; 
3. Have advanced or metastatic melanoma incurable by standard of care therapies; 

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4. Have received a combination of a BRAF inhibitor and a MEK inhibitor if diagnosed with a 
BRAF-mutated melanoma and if clinically indicated; and 
5. Have failed or progressed on or after treatment with a checkpoint inhibitor administered either 
as monotherapy or in combination with other checkpoint inhibitors or other therapies. 
Inclusion Criteria for Arm C 
Patients who meet all of the general Inclusion Criteria and the following additional criteria will be 
eligible for inclusion in Arm C: 
1. Have histologically confirmed diagnosis of TNBC as per American Society of Clinical 
Oncology/College of American Pathologists guidelines;  
2. Have advanced or metastatic TNBC incurable by standard of care therapies; 
3. Have received sacituzumab govitecan chemotherapeutic treatment if clinically indicated; and 
4. Have failed or progressed on or after treatment with a checkpoint inhibitor administered either 
as monotherapy or in combination with other therapies (if ICI eligible based on programmed 
cell death ligand 1 [PD-L1] status) OR have received prior systemic therapy with either an 
anthracycline- or taxane-containing regimen (if ICI non-eligible based on PD-L1 status). 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Have only non-palpable cutaneous infiltrations (eg, breast cancer cutaneous carcinomatosis); 
2. Have had anti-cancer therapy within 4 weeks prior to the first dose of study treatment (2 weeks 
for palliative radiotherapy); 
Note: Patients must have recovered from all adverse events (AEs) due to previous therapies to 
Grade 1 or baseline (alopecia is an allowable exception). Upon discussion with the Sponsor, 
patients with Grade 2 neuropathy or endocrine-related AEs requiring treatment or hormone 
replacement may be eligible. 
Note: If the patient had major surgery, the patient must have recovered adequately from the 
procedure and/or any complications from the surgery prior to starting study intervention. 
3. Have participated in a clinical trial and received an investigational therapy within 30 days prior 
to the first dose of study treatment; 
4. Have received or will receive a live or live attenuated vaccine within 30 days prior to the first 
dose of study treatment;  
Note: Seasonal flu vaccines that do not contain live vaccine are permitted. Coronavirus 
Disease 2019 (COVID-19) vaccines are only permitted with documentation of the date of the 
vaccine if the last dose of vaccine was administered >14 days prior to the first dose of study 
treatment. The COVID-19 booster vaccine must be administered at least 14 days prior to the 
first dose of study treatment and is not allowed during the first 3 months of the Treatment 
Period. 

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5. Have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection within 14 days prior to the Screening Visit; 
Note: Patients who have had a known SARS-CoV-2 infection >14 days prior to the Screening 
Visit are permitted at Investigator discretion and must present with no symptoms. 
6. Have had a major surgical procedure within 14 days prior to the first dose of study treatment; 
7. Are expected to require a systemic or localized anti-neoplastic therapy during participation in 
this study, excluding localized palliative radiotherapy to tumors not selected for evaluation of 
treatment response; 
Note: Use of denosumab for patients with bone metastasis is allowed. 
8. Are pregnant or breastfeeding; 
9. Have clinical evidence of a secondary malignancy actively progressing or requiring active 
treatment other than curative therapies for early stage (carcinoma in situ or Stage 1) 
carcinomas or non-melanoma skin cancer; 
10. Have had any autoimmune disease requiring immunosuppressive therapy (ie, use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs) within 2 years prior to the 
first dose of study treatment;  
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is allowed.  
11. Have a condition requiring continuous systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive agents within 2 weeks prior to the 
first dose of study treatment. Inhaled, intranasal, or topical (only on areas outside the injected 
lesion[s]) and physiological replacement doses of up to 10 mg daily prednisone equivalent are 
permitted in the absence of active autoimmune disease; 
12. Have abnormal or clinically significant coagulation parameters as determined by the 
Investigator (eg, prothrombin time, international normalized ratio, activated partial 
thromboplastin time) unless patients are on anti-coagulants in which case it must be within 
appropriate clinical levels; 
Note: Patients who are on anti-coagulants must be able to switch to a low molecular weight 
heparin or equivalent prior to Cycle 1 Day 1 and continue during the Treatment Period. 
13. Have a significant history or clinical manifestation of any allergic disorders and/or Quincke¶s 
edema (as determined by the Investigator) capable of significantly altering the absorption of 
drugs, of constituting a risk when taking CyPep-1 or pembrolizumab, or of interfering with the 
interpretation of the data; 
14. Have a known hypersensitivity to any component of CyPep-1 or pembrolizumab; 
15. Have a history of adverse reactions from treatment with ICIs, including pembrolizumab, which 
resulted in discontinuation of ICI or pembrolizumab or has ongoing pembrolizumab-related 
toxicity event(s) as per treatment-limiting toxicity definitions, except patients with ongoing 

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endocrine disorders that are managed with replacement therapy (ie, hypothyroidism related to 
prior pembrolizumab treatment); 
16. Have an active infection requiring systemic therapy; 
17. Have a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known 
active Hepatitis C virus (defined as Hepatitis C virus RNA [qualitative] is detected) infection; 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health 
authority. 
18. Have had radiotherapy within 2 weeks prior to the first dose of study treatment, are in recovery 
from radiation toxicity, or have had radiation pneumonitis; 
19. Have a history of non-infectious pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease; 
20. Have had a prior allogeneic tissue/solid organ transplant, stem cell, or bone marrow transplant; 
21. Have active human immunodeficiency virus (HIV). Patients are eligible when on stable 
anti-retroviral therapy (no change in medication or dose) for at least 4 weeks prior to screening, 
have confirmed virologic suppression with HIV RNA less than 50 copies/mL or the lower 
limit of quantification (below the limit of detection) using the locally available assay at the 
time of screening and for at least 12 weeks prior to screening, and have a cluster of 
differentiation 4+ T cell count >350 cells/mm3 at screening. HIV-infected patients with a 
history of Kaposi sarcoma and/or Multicentric Castleman Disease will be excluded; 
22. Have 4 or more sites involved, including the primary cancer; 
Note: A site is defined as an organ (eg, lung, liver, or brain) or a system (eg, lymphatic or 
central nervous system [CNS]). 
23. Have a CNS metastasis that is symptomatic, progressing, or that requires current therapy (eg, 
evidence of new or enlarging CNS metastasis, carcinomatous meningitis, or new neurological 
symptoms attributable to CNS metastasis); 
24. Have a QTcF >480 ms at screening, history of long or short QT syndrome, Brugada syndrome, 
QTc prolongation, or Torsade de Pointes, with the exception of patients with controlled atrial 
fibrillation, pacemaker, or bundle branch block as the QTc will be prolonged due to the 
widened QRS; 
25. Are an adult under legal protection, are vulnerable, or lack the capacity to give informed 
consent, such as: 
o Persons deprived of liberty by a judicial or administrative decision; 
o Adult persons subject to a legal protection measure (under supervision/under 
guardianship); or  
o Persons under a judicial protection measure; or 
26. Have a history of 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 make participation in the study not in the best interest of the patient, 
in the opinion of the Investigator. 

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STUDY DESIGN AND DURATION: 
This is an open-label, multi-center, non-randomized Phase 1b/2a study. The Phase 1b portion of 
the study (ie, the first 6 patients enrolled) will confirm the recommended CyPep-1 dose of 20 mg 
every 2 weeks (Q2W) in combination with pembrolizumab 400 mg every 6 weeks (Q6W). The 
patients from the Phase 1b portion will continue to the Phase 2a portion of the study 
(approximately 90 patients in total will be enrolled, with 30 patients per arm). The Phase 2a 
portion of the study will have 3 arms including patients with advanced or metastatic HNSCC, 
melanoma, or TNBC and will assess the efficacy, safety, and pharmacodynamics of CyPep-1 
(20 mg Q2W) when administered directly into measurable tumor lesions in combination with the 
anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab (400 mg Q6W).  
After signing the ICF, patients will be assessed for study eligibility. The Screening Visits will be 
completed within 28 days of the start of treatment. Screening will include the identification of 
measurable tumor lesions as per RECIST v1.1. Patients with lesions appropriate for IT injection 
with CyPep-1 (injected lesions) should be identified and will receive up to 4 mL of CyPep-1, after 
it is ensured that they meet the Inclusion Criteria and none of the Exclusion Criteria per the 
Investigator.  
When more than 1 measurable lesion is present at screening, up to a maximum of 5 lesions total 
(and a maximum of 2 lesions per organ) representative of all involved organs should be identified 
as target lesions. Both injected and non-injected lesions identified at screening per RECIST v1.1 
may be target lesions and will be recorded and measured at baseline and followed for response. If 
a patient only has 1 measurable lesion, then this lesion will be identified as an injected lesion and 
will be evaluated for efficacy as a target lesion. In these cases, IT therapy will not be considered 
a loco-regional therapy exclusionary for measurability, and single lesions may be designated as 
injectable target lesions per intratumoral-RECIST (itRECIST). 
After each of the first 3 CyPep-1 injections, a telephone call will be conducted once daily for the 
first 2 days and once approximately 1 week post injection to assess patients¶ symptoms and 
temperatures. 
AEs will be recorded from the time of signing the ICF until 30 days after the last dose of study 
treatment. All AEs that are considered serious will be monitored and recorded until 90 days 
(30 days if patients initiate new anti-cancer therapy) after the last dose of study treatment. Other 
safety assessments will be conducted as described in the Schedule of Assessments. The Data 
Monitoring Committee (DMC) will review accumulating safety data in regular intervals as per the 
DMC charter. 
Phase 1b 
The Phase 1b portion of the study will comprise of the first 6 patients enrolled in the study to 
confirm the recommended CyPep-1 dose (20 mg Q2W) based on safety and tolerability 
observations.  
Patients will receive IT injections of a fixed concentration of CyPep-1 Q2W beginning at Cycle 1 
Visit 1. Pembrolizumab will be administered intravenously (IV) at a fixed dose Q6W beginning 
at Cycle 1 Visit 1. Patients must be observed for 4 hours post injection for pharmacokinetic (PK) 
monitoring on Cycle 1 Day 15. The plasma concentration-time profile of CyPep-1 and, if 
detectable, the derived PK parameters will be assessed. 

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The dose-limiting toxicity (DLT) period for the Phase 1b portion of the study will be Cycle 1 
(initial 6 weeks of study treatment). After the first 6 patients have completed the DLT period, the 
DMC and Sponsor will review safety and tolerability data prior to the enrollment of the patients 
into the Phase 2a portion of the study. If 2 DLTs are observed in the first 6 patients, then the 
recommended CyPep-1 dose will be confirmed and enrollment of the remainder of the patients 
should continue. 
If >2 of the 6 patients develop a DLT at the recommended CyPep-1 dose level (5 mg/mL dose 
concentration), then the maximum tolerated dose (MTD) of CyPep-1 will be assumed to have been 
exceeded and dose de-escalation will be conducted to determine the MTD. At least 6 patients will 
be treated at CyPep-1 dose level -1 (2 mg/mL dose concentration). If necessary, due to >2 DLTs 
in the dose level -1 cohort, a further reduction to dose level -2 (0.5 mg/mL dose concentration) 
will be performed. 
Dose de-escalation will proceed according to the following rules: 
 If 2 out of 6 patients develop a DLT, the MTD will be declared; or 
 If >2 out of 6 patients develop a DLT, the dose will be de-escalated to the next lower dose. 
The MTD will guide confirmation, by agreement of the DMC and the Sponsor, of a recommended 
Phase 2 dose (RP2D). The RP2D may be equivalent to the MTD or may be a dose below the MTD 
and will be dependent on an acceptable tolerability profile and manageable AEs. 
The patients from Phase 1b will continue to the Phase 2a portion of the study. After the DMC 
reviews the safety data, feedback will be provided to the Sponsor regarding the further conduct of 
the study. 
Dose-limiting toxicities 
All toxicities will be graded using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0 based on the Investigator assessment. 
The DLT window of observation will be during Cycle 1 (initial 6 weeks of study treatment). 
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the Investigator to be possibly, probably, or definitely related to study treatment 
administration:  
1. Grade 4 non-hematologic toxicity (not laboratory); 
2. Grade 4 hematologic toxicity lasting 7 days, except thrombocytopenia: 
o Grade 4 thrombocytopenia of any duration; or 
o Grade 3 thrombocytopenia associated with clinically significant bleeding. 

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3. Any non-hematologic AE Grade 3 in severity should be considered a DLT, with the following 
exceptions:  
o Grade 3 fatigue lasting 3 days;  
o Grade 3 diarrhea, nausea, or vomiting unless it persists for >3 days despite the use of 
anti-emetics or anti-diarrheals per standard of care; or 
o Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of 
care. 
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
o Clinically significant medical intervention is required to treat the patient; 
o The abnormality leads to hospitalization; 
o The abnormality persists for >1 week; or 
o The abnormality results in a drug-induced liver injury.  
o Exceptions: Clinically non-significant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc. Isolated laboratory abnormalities Grade 3 
(not present at baseline) that resolve to <Grade 1 in <3 days without clinical sequelae or 
need for therapeutic intervention. 
5. Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for more 
than 1 hour; or 
o Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) or a 
sustained temperature of 38°C (100.4°F) for more than 1 hour with life-threatening 
consequences and urgent intervention indicated. 
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; 
7. Delay in administration of CyPep-1 for >7 days; 
8. Any single instance of aspartate aminotransferase and/or alanine aminotransferase >3 × upper 
limit of normal (ULN) AND concurrent total bilirubin >2 × ULN that is not thought to be due 
to disease progression or other medical illness (ie, liver function abnormalities that meet the 
criteria of Hy¶s Law); 
9. Any treatment-related toxicity that causes the patient to discontinue treatment during Cycle 1; 
10. Missing >25% of study treatment doses as a result of drug-related AE(s) during the first cycle; 
or 
11. Grade 5 toxicity. 
Phase 2a 
The Phase 2a portion of the study will comprise of all approximately 90 patients (including the 
first 6 patients assessed in the Phase 1b portion) to assess the efficacy, safety, and 
pharmacodynamics of CyPep-1 (20 mg Q2W) in combination with the anti-PD-1 antibody 

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pembrolizumab (400 mg Q6W). Patients will receive IT injections of a fixed concentration of 
CyPep-1 Q2W beginning at Cycle 1 Visit 1. Pembrolizumab will be administered IV at a fixed 
dose Q6W beginning at Cycle 1 Visit 1. Each treatment cycle will be 6 weeks, and treatment will 
continue for a maximum of 18 cycles (108 weeks) or until the occurrence of confirmed progressive 
disease (PD), excessive toxicity, death, or withdrawal of consent. Patients who complete all 
18 cycles, which is the Food and Drug Administration-approved maximum duration of 
pembrolizumab use, may continue receiving CyPep-1 at the current dose if determined beneficial 
by the Investigator and following approval of the Sponsor. CyPep-1 monotherapy may proceed 
until the occurrence of confirmed PD, excessive toxicity, death, or withdrawal of consent.  
Radiological assessments and local measurements of tumor lesion(s), according to RECIST v1.1, 
will be conducted and evaluated at baseline (screening) and at 8-week intervals after the first dose 
of CyPep-1 through the last Progression Follow-up Visit during the Follow-up Period (up to 
approximately 26 months after the start of treatment). Radiological assessments can be more 
frequent if clinically indicated. Magnetic resonance imaging (MRI) or computed tomography (CT) 
are the preferred scanning procedures to be used in this study. Selection of either MRI or CT 
should be based on individual patient considerations and local regulations and is at the 
Investigator¶s discretion. Once selected for each patient, the same scanning procedure should be 
used consistently at all remaining visits. Scans will be collected and held centrally for potential 
central radiologic review. When radiological PD is identified by the Investigator, PD is to be 
confirmed by another set of scans performed approximately 4 weeks to 8 weeks later according 
to immune-RECIST (iRECIST) guidelines. If PD is not confirmed, study treatment will continue 
until progression is confirmed.  
Patients who have confirmed PD or discontinue treatment for any other reason will be followed-up 
by phone call every 3 months for survival until the end of study (approximately 26 months after 
the start of treatment).  
Unless death or withdrawal of consent occurs, patients who received any injection of CyPep-1 
will have a Safety Follow-up Visit 30 days after the last CyPep-1 injection. If the End of Treatment 
Visit occurs more than 30 days after the last dose of study treatment, the Safety Follow-up Visit 
will be skipped. Patients who terminate treatment prior to 18 cycles will continue to be followed 
for progression every 8 weeks from start of study treatment until the occurrence of confirmed PD 
as defined by iRECIST or start of new anti-cancer treatment. These patients will also be followed 
for survival for up to approximately 26 months after the start of treatment.  
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The overall study treatment regimen is defined as IT CyPep-1 in combination with IV 
pembrolizumab. 
CyPep-1 Administration 
CyPep-1 will be administered Q2W as an IT injection. CyPep-1 will be administered through a 
needle, which should be redirected along multiple tracks to ensure even dispersion of CyPep-1 
throughout the tumor lesion. On the visits that CyPep-1 and pembrolizumab are administered on 
the same day, CyPep-1 is to be administered 30 to 60 minutes after pembrolizumab infusion is 
completed. Following CyPep-1 administration, patients must be observed for 4 hours post 
injection at Cycle 1 Visit 1 and Cycle 2 Visit 1 and 1 hour post injection at Cycle 1 Visit 2 and 

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Cycle 1 Visit 3 for potential immediate injection-related reactions. Refer to the Guidance for 
Intra-tumoral Administration of CyPep-1 study manual for more details.  
The cumulative maximal injected volume of CyPep-1 will be 4 mL (cumulative maximal dose of
20 mg at the recommended 5 mg/mL concentration) per treatment day for each patient, and it may 
be divided for injection over 1 to 3 tumor lesions (satellitosis/grouped lesions <1 cm count as 
1 lesion) depending on tumor lesion size; see Table S3. The injected lesions identified at baseline 
should be injected 3 times before selecting new lesions to inject, unless there is a complete 
response or the lesion, by the Investigator¶s assessment, has been adequately treated (eg, reduced 
size and highly inflamed). The volume of CyPep-1 delivered to each injected lesion will be 
determined based on the longest diameter of the lesion. Effort should be made to administer the 
maximum volume of CyPep-1 as planned per lesion size; see Table S3.  
Table S3. Approximate Injected CyPep-1 Volume per Lesion Size 
Measured Lesion Diameter (cm) 
Injected Volume (mL) 
0.79 
0.1 
0.80-0.99 
0.2 
1.00-1.24 
0.5 
1.25-1.50 
1.5 
1.51-2.49 
3.0 
2.50-5.00 
4.0 
Pembrolizumab Administration 
The dose of pembrolizumab in combination with CyPep-1 will be 400 mg Q6W administered via 
a 30-minute infusion, beginning at Cycle 1 Visit 1. On the visits that CyPep-1 and pembrolizumab 
are administered on the same day, CyPep-1 is to be administered 30 to 60 minutes after
pembrolizumab infusion is completed. Pembrolizumab may be administered up to 3 days before 
or after the scheduled Visit 1 of each cycle from Cycle 2 onward.  
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
SAFETY VARIABLES: 
Safety will be assessed by physical examinations, vital signs, 12-lead electrocardiograms (ECGs), 
ECOG performance status, laboratory evaluations, and AEs (as defined by NCI CTCAE v5.0) as 
indicated in the Schedule of Assessments. Additional assessments may be performed as clinically 
indicated.  
Safety will be monitored in conjunction with the DMC and as per DMC charter.  
STATISTICAL ANALYSES: 
Analysis Sets 
The Full Analysis Set (FAS) will include all patients who receive an injection of CyPep-1. The 
FAS will be used in the analysis of efficacy and exploratory endpoints. 
The Evaluable Analysis Set (EAS) will include all patients who receive an injection of CyPep-1 
on at least 2 treatment days, receive at least 1 administration of pembrolizumab, and have at least 
1 post-baseline tumor response assessment after the first injection of CyPep-1 (Cycle 1 Visit 1). 
Table S3. Approximate Injected CyPep-1 Volume per Lesion Size 
Measured Lesion Diameter (cm) 
Injected Volume (mL) 
0.79 
0.1 
0.80-0.99 
0.2 
1.00-1.24 
0.5 
1.25-1.50 
1.5 
1.51-2.49 
3.0 
2.50-5.00 
4.0 

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The Safety Analysis Set (SAS) will include all patients who receive at least 1 injection of CyPep-1 
or at least 1 administration of pembrolizumab. The SAS will be the basis of safety analyses.  
Analysis of Efficacy 
Analysis of efficacy will be conducted in Phase 2a. Efficacy analyses will be done using the FAS. 
The Objective Response Rate (ORR) will be based on the number of patients achieving a partial 
response (PR) or complete response (CR) based on RECIST v1.1 and iRECIST. Best overall 
response will also be calculated. The Disease Control Rate will be based on the number of patients 
achieving a PR, CR, or stable disease 
16 weeks based on RECIST v1.1 and iRECIST. 
Progression Free Survival (PFS) (percentage of patients alive and progression-free) at 6, 12, 18, 
and 24 months after the first treatment with CyPep-1 + pembrolizumab will be determined. A 
progression event is defined as disease relapse or progression (based on all lesions) or death due 
to any cause. For patients who are not known to have died or progressed as of the data cut-off date, 
PFS will be censored at the date of the last objective progression-free disease assessment. Patients 
who discontinue the study treatment without post-treatment assessments will be treated as 
non-responders. The detailed censoring rules will be specified in the Statistical Analysis Plan. 
Sensitivity analysis for primary efficacy endpoints will be provided using the EAS. An exploratory 
analysis of itRECIST will be applied to allow for a separate response assessment of injected and 
non-injected lesions. 
Analysis of Safety 
Safety analysis will be conducted in both Phase 1b and Phase 2a using the SAS. 
Treatment-emergent AE (TEAE) incidence rates will be described by the frequency of TEAEs and 
categorized by preferred term and system organ class according to the NCI CTCAE v5.0. TEAEs 
will be summarized by seriousness, grade, and relationship to CyPep-1 and pembrolizumab. The 
incidence of TEAEs will be evaluated for each study arm and for all patients combined. The 
following data will be summarized using descriptive statistics: treatment exposure, disposition, 
vital signs, body weight, 12-lead ECG parameters, and laboratory assessments. Shift tables 
showing changes from baseline will be generated where appropriate. Summaries will be by arm 
and for all patients. 
The incidence of DLT events during the DLT period will be presented. 
Analysis of Pharmacokinetics 
Phase 1b patients who have received CyPep-1 and have provided 1 evaluable pre-dose and at least 
1 post-dose PK blood sample will be evaluable for PK. Standard methodology will be used to 
estimate PK parameters. Concentration-time profiles will be derived for patients with post-dose 
samples. 
SAMPLE SIZE DETERMINATION: 
The Simon¶s 2-Stage Design is used in the Phase 2 portion, which allows the study to be stopped 
for futility and provides a recommendation for continuation from Stage 1 to Stage 2.  
CATALYST is a hypothesis-generating study for the combination of CyPep-1 with 
pembrolizumab. The hypothesis implemented in the Simon¶s 2-Stage Design disease model uses 
the historical objective responses observed in pembrolizumab single-agent Phase 2 trials. The 

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rationale and statistical details are provided in the key references of the 3+3 dose-escalation design 
for Phase 1 trials in oncology. 
The sample size for the Phase 1b portion of the study is based on practical determinations. The 
first 6 patients of the study are planned to be enrolled in the Phase 1b portion. Approximately 
90 patients will be enrolled, with 30 patients per arm. Assuming 10% of enrolled patients will not 
have evaluable post-baseline tumor response data, it is expected that approximately 27 patients 
will be included in the evaluable set in each arm. 
While all endpoints will be reviewed to assess activity of CyPep-1, and the sample size is based 
on practical rather than statistical considerations, the level of precision that is achieved for 
27 patients on the primary endpoint, ORR, is as follows: 
A sample size of 27 patients will produce a 2-sided exact 80% confidence interval of 34.4% to 
62.0% when the sample proportion is 48% (13/27) and an interval of 38.1% to 65.5% when the 
sample proportion is 52% (14/27). The lower bounds are computed through an exact binomial test. 
The Simon¶s 2-Stage Design will be used in the Phase 2 portion to determine whether CyPep-1 
has sufficient anti-tumor activity to warrant further development for patients with advanced or 
metastatic HNSCC, melanoma, or TNBC. A true ORR 9% is considered insufficient to warrant 
further study (null hypothesis), whereas a true ORR 25% is considered sufficiently effective 
(alternative hypothesis). The number of patients in each stage and the minimum number of patients 
achieving objective response (CR + PR) per RECIST v1.1 needed to continue to the next stage 
will be determined based on the Simon¶s 2-Stage Design with 80% power and a 1-sided 
significance level of 10% for each arm separately. Based on this design, up to 16 evaluable patients 
will be accrued for Stage 1. If 
1 patient of these 16 patients achieves objective response 
(CR + PR) per RECIST v1.1, the enrollment for the expansion cohort will terminate. Otherwise, 
10 additional evaluable patients will be evaluated in Stage 2. In order to enroll the required number 
of evaluable patients, it is anticipated that approximately 18 and 12 patients (total of approximately 
30 patients) will be enrolled into Stages 1 and 2, respectively. Upon completion of Stage 2, if 
>4 patients out of the total 26 evaluable patients achieve objective response (CR + PR) per 
RECIST v1.1, then the null hypothesis will be rejected. If the required minimum number of 
responses is observed prior to completion of enrollment, then the transition between the first and 
second stages will occur without interruption. If the minimum is not observed at the time 
enrollment is completed, then enrollment in the second stage will be held until the continuation 
criterion is met. 
SITES:  Approximately 35 study sites 
SPONSOR: 
Cytovation ASA 
Solheimsgaten 11 
5058 Bergen 
Norway 
Telephone: +47 477 18 809 

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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2
Investigator Agreement ................................................................................................................... 3
Synopsis .......................................................................................................................................... 4
Table of Contents .......................................................................................................................... 18
List of Tables ................................................................................................................................ 22
List of Figures ............................................................................................................................... 23
List of Abbreviations and Definition of Terms............................................................................. 24
1
Introduction and Background Information ............................................................................. 27
1.1
Preclinical and Clinical Data Summary ........................................................................ 27
1.1.1
Preclinical Studies With CyPep-1 ..................................................................... 27
1.1.2
Clinical Studies With CyPep-1 ......................................................................... 28
1.2
Rationale ........................................................................................................................ 33
1.3
Risk/Benefit ................................................................................................................... 34
1.3.1
Potential Risks ................................................................................................... 34
1.3.2
Benefit ............................................................................................................... 35
1.4
Coronavirus Disease 2019 Impacts ............................................................................... 35
2
Study Objectives and Endpoints ............................................................................................. 36
3
Study Description.................................................................................................................... 38
3.1
Summary of Study Design ............................................................................................ 38
3.1.1
Phase 1b ............................................................................................................. 40
3.1.1.1
Dose-limiting toxicities ....................................................................... 41
3.1.2
Phase 2a ............................................................................................................. 42
3.1.3
Data Monitoring Committee ............................................................................. 43
3.1.4
Coronavirus Disease 2019 Contingency Measures ........................................... 44
3.2
Study Indications ........................................................................................................... 44
4
Selection and Withdrawal of Patients ..................................................................................... 45
4.1
Inclusion Criteria ........................................................................................................... 45
4.1.1
General Inclusion Criteria ................................................................................. 45
4.1.2
Inclusion Criteria for Arm A ............................................................................. 46
4.1.3
Inclusion Criteria for Arm B ............................................................................. 47

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4.1.4
Inclusion Criteria for Arm C ............................................................................. 47
4.2
Exclusion Criteria .......................................................................................................... 47
4.3
Retesting ........................................................................................................................ 50
4.4
Rescreening ................................................................................................................... 50
4.5
Withdrawal Criteria ....................................................................................................... 50
4.5.1
Discontinuation of Study Treatment ................................................................. 50
4.5.2
Discontinuation From the Study ....................................................................... 51
4.5.3
Discontinuation of Enrollment Criteria ............................................................. 51
5
Study Treatments .................................................................................................................... 53
5.1
Treatment Groups .......................................................................................................... 53
5.2
Rationale for Dosing ..................................................................................................... 53
5.2.1
CyPep-1 ............................................................................................................. 53
5.2.2
Pembrolizumab .................................................................................................. 54
5.3
Randomization and Blinding ......................................................................................... 54
5.4
Breaking the Blind ........................................................................................................ 54
5.5
Drug Supplies ................................................................................................................ 55
5.5.1
Formulation and Packaging ............................................................................... 55
5.5.2
Study Drug Preparation and Handling .............................................................. 55
5.5.3
Study Drug Administration ............................................................................... 55
5.5.3.1
CyPep-1 administration ...................................................................... 55
5.5.3.2
Pembrolizumab administration ........................................................... 56
5.5.3.3
Dose modification and toxicity management ..................................... 57
5.5.3.4
Overdose ............................................................................................. 63
5.5.4
Treatment Compliance ...................................................................................... 63
5.5.5
Storage and Accountability ............................................................................... 63
5.6
Prior and Concomitant Medications and/or Procedures ................................................ 64
5.6.1
Excluded Medications and/or Procedures ......................................................... 64
5.6.2
Restricted Medications and/or Procedures ........................................................ 64
5.6.3
Allowed Medications and/or Procedures .......................................................... 65
5.6.4
Documentation of Prior and Concomitant Medication Use .............................. 65
5.6.5
Dietary Restrictions ........................................................................................... 66
6
Study Procedures .................................................................................................................... 67

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7
Efficacy Assessments .............................................................................................................. 68
7.1
Local Measurement of Tumor Lesions ......................................................................... 68
7.2
Radiological Assessment ............................................................................................... 68
7.3
Tumor Biopsy ................................................................................................................ 69
7.4
Pharmacokinetic Sampling ............................................................................................ 69
8
Safety Assessments ................................................................................................................. 70
8.1
Adverse Events .............................................................................................................. 70
8.1.1
Adverse (Drug) Reaction .................................................................................. 71
8.1.2
Unexpected Adverse Drug Reaction ................................................................. 71
8.1.3
Assessment of Adverse Events by the Investigator .......................................... 71
8.1.4
Adverse Events of Clinical Interest ................................................................... 73
8.2
Serious Adverse Events ................................................................................................. 73
8.3
Serious Adverse Event Reporting  Procedures for Investigators ................................ 74
8.4
Pregnancy Reporting ..................................................................................................... 75
8.5
Expedited Reporting ...................................................................................................... 75
8.6
Special Situation Reports .............................................................................................. 76
8.7
Clinical Laboratory Evaluations .................................................................................... 77
8.8
Vital Signs ..................................................................................................................... 77
8.9
Electrocardiograms ........................................................................................................ 77
8.10 Height, Weight, and Physical Examinations ................................................................. 78
8.11 Eastern Cooperative Oncology Group Performance Status .......................................... 78
8.12 Pregnancy Test .............................................................................................................. 78
8.13 Thyroid Function Testing .............................................................................................. 79
9
Statistics .................................................................................................................................. 80
9.1
Analysis Sets ................................................................................................................. 80
9.2
Statistical Methods ........................................................................................................ 80
9.2.1
Analysis of Efficacy .......................................................................................... 80
9.2.2
Analysis of Safety ............................................................................................. 80
9.2.3
Analysis of Pharmacokinetics ........................................................................... 81
9.2.4
Sample Size Determination ............................................................................... 81
10 Data Management and Record Keeping ................................................................................. 83
10.1 Data Management ......................................................................................................... 83

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10.1.1 Data Handling ................................................................................................... 83
10.1.2 Computer Systems ............................................................................................. 83
10.1.3 Data Entry ......................................................................................................... 83
10.1.4 Medical Information Coding ............................................................................. 83
10.1.5 Data Validation ................................................................................................. 83
10.2 Record Keeping ............................................................................................................. 83
10.3 End of Study .................................................................................................................. 84
11 Investigator Requirements and Quality Control ..................................................................... 85
11.1 Ethical Conduct of the Study ........................................................................................ 85
11.2 Institutional Review Board/Independent Ethics Committee ......................................... 85
11.3 Informed Consent .......................................................................................................... 85
11.4 Subject Card .................................................................................................................. 86
11.5 Study Monitoring Requirements ................................................................................... 86
11.6 Disclosure of Data ......................................................................................................... 86
11.7 Retention of Records ..................................................................................................... 86
11.8 Publication Policy ......................................................................................................... 87
11.9 Financial Disclosure ...................................................................................................... 87
11.10 Insurance and Indemnity ............................................................................................... 87
11.11 Legal Aspects ................................................................................................................ 87
11.12 Conflict of Interest Policy ............................................................................................. 87
12 Study Administrative Information .......................................................................................... 88
12.1 Protocol Amendments ................................................................................................... 88
13 References ............................................................................................................................... 89
Appendix A:  Schedule of Assessments ....................................................................................... 91
Appendix B:  Clinical Laboratory Analytes ................................................................................. 95
Appendix C:  Eastern Cooperative Oncology Group Performance Status Scoring ...................... 97
Appendix D:  Description of the iRECIST Process for Assessment of Disease Progression ....... 98
Appendix E:  itRECIST Guidance .............................................................................................. 102

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LIST OF TABLES 
Table 1.
Individual CyPep-1 Concentrations (ng/mL) by Time (CICILIA Study) .................. 30
Table 2.
Individually Computed Single-Dose Pharmacokinetic Parameters Based on CyPep-1 
Concentrations (CICILIA Study) ................................................................................ 30
Table 3.
Descriptive Statistics of Computed Pharmacokinetic Parameters by Cohort (CICILIA 
Study) .......................................................................................................................... 31
Table 4.
Cumulative Treatment-Emergent Adverse Events and CyPep-1-Related 
Treatment-Emergent Adverse Events by Preferred Term (CICILIA Study) .............. 32
Table 5.
Frequency of Reported Treatment-Emergent Adverse Events per Dose Cohort 
(CICILIA Study) ......................................................................................................... 33
Table 6.
Objectives and Endpoints ........................................................................................... 36
Table 7.
Adequate Organ Function Laboratory Values ............................................................ 46
Table 8.
Dose Cohorts ............................................................................................................... 54
Table 9.
Approximate Injected CyPep-1 Volume per Lesion Size ........................................... 56
Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related AEs 
Associated With Pembrolizumab ................................................................................ 59
Table 11. Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines .... 62
 
 

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LIST OF FIGURES 
Figure 1.
Individual Time-Serum Profiles for CyPep-1 (CICILIA Study) ................................ 31
Figure 2.
One-Stage Study Design ............................................................................................. 39
Figure 3.
Study Flow .................................................................................................................. 40

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AECI 
Adverse event of clinical interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO/CAP 
American Society of Clinical Oncology/College of American
Pathologists 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
Cmax 
Peak plasma concentration 
CNS 
Central nervous system 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete response 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTA 
Clinical trial authorization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEC 
Dose Escalation Committee 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DRF 
Dose range finding 
EAS 
Evaluable Analysis Set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
EoT 
End of Treatment  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 

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Abbreviation 
Definition 
IB 
Investigator¶s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICI 
Immune checkpoint inhibitor 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
Immune-Response Evaluation Criteria in Solid Tumors 
IT 
Intra-tumoral(ly) 
itRECIST 
Intratumoral-Response Evaluation Criteria in Solid Tumors 
IV 
Intravenous(ly) 
LOQ 
Limit of quantification 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PT 
Prothrombin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q6W 
Every 6 weeks 
Q8W 
Every 8 weeks 
QTc 
Heart rate-corrected QT interval 
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 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Safety Analysis Set 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 

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Abbreviation 
Definition 
Tmax 
Time to reach peak plasma concentration 
TNBC 
Triple-negative breast cancer 
ULN 
Upper limit of normal 
v 
Version 

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1
INTRODUCTION AND BACKGROUND INFORMATION 
Treatment with immune checkpoint inhibitors (ICIs) has been shown to result in long-lasting 
anti-tumor responses in selective subjects with different tumor indications. However, only a subset 
of these subjects obtains durable remission. Several studies have previously indicated the presence 
of intra-tumoral (IT) cluster of differentiation (CD)8+ T cells to be a positive predictive factor for 
response to ICI therapy.1,2,3,4 Thus, treatment strategies aimed at recruiting tumor-antagonizing 
cellular components of the immune system hold great promise and are currently the main focuses 
in oncology research.5
Therapeutic studies in mouse models have shown that administration of antibodies that block the 
programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction 
enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, either 
as a monotherapy or in combination with other treatment modalities.6,7,8,9,10,11,12 Anti-mouse PD-1 
or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses in models of squamous 
cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia, and colorectal 
carcinoma.9,11,12,13,14 In such studies, tumor infiltration by CD8+ T cells and increased interferon 
gamma, granzyme B, and perforin expression were observed, indicating that the mechanism 
underlying the anti-tumor activity of PD-1 checkpoint inhibition involved local infiltration and 
activation of effector T cell function in vivo.11 Experiments have confirmed the in vivo efficacy of 
anti-mouse PD-1 antibody as a monotherapy, as well as in combination with chemotherapy, in 
syngeneic mouse tumor models.15
Current evidence reveals an association between mutational tumor burden and tumor 
immunogenicity.16,17,18 In order to grow, antigenic tumors must develop mechanisms that enable 
them to evade immune-mediated destruction through a process termed immunoediting.19 However, 
while mutational load represents a predictive factor for ICI therapy,20,21 its predictive power is 
modest; rather, it seems associated with the presence of specific neoantigen-generating 
mutations.16 This observation, supported by both preclinical- and clinical-evidence, suggests that 
a qualitative neoantigen-directed immunotherapy holds great potential. New therapeutic 
modalities in this category should ideally meet 2 critical criteria: 1) display tumor-specific antigens 
and 2) induce an inflamed tumor microenvironment. Furthermore, the capacity of such therapeutic 
modalities may result in an extended patient population of responders and potentially increase the 
overall efficacy of ICIs. 
CyPep-1 is an engineered synthetic peptide with oncolytic properties. It consists of 27 amino acids 
and specifically targets tumor cells due to their altered electrochemical properties while leaving 
normal cells intact. CyPep-1 modulates the tumor microenvironment by increasing the presence 
of CD8+ T cells and potentiates the effects of ICIs. CyPep-1 is an amorphous white to off-white 
powder, with no crystalline or polymorphic forms identified to date. The molecular mass of 
CyPep-1, as determined based on a combination of electrospray ionization-mass spectrometry and 
amino acid analysis, is 3492.2 Daltons. 
1.1
Preclinical and Clinical Data Summary 
1.1.1
Preclinical Studies With CyPep-1 
In animal studies, CyPep-1 was administered intravenously (IV) (0.5 mg/kg to 20 mg/kg in rats 
and 0.1 mg/kg to 7 mg/kg in dogs) or topically (formulated as 1.0% cream). For all Good 
Laboratory Practice studies, the test products contained CyPep-1 alone or with compendial 
1
INTRODUCTION AND BACKGROUND INFORMATION 
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p
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(
)
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p
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cellular components of the immune system hold great promise and are currently the main focuses 
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in oncology research.5
Therapeutic studies in mouse models have shown that administration of antibodies that block the 
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g
(
)
enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, either 
p
y
as a monotherapy or in combination with other treatment modalities.6,7,8,9,10,11,12
j
,
Anti-mouse PD-1 
py
or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses in models of squamous 
p
q
cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia, and colorectal 
carcinoma.
, p
9,11,12,13,14
,
,
y
,
In such studies, tumor infiltration by CD8+ T cells and increased interferon 
,
y
gamma, granzyme B, and perforin expression were observed, indicating that the mechanism 
g
, g
y
,
p
p
,
g
underlying the anti-tumor activity of PD-1 checkpoint inhibition involved local infiltration and 
y g
y
activation of effector T cell function in vivo.11
p
Experiments have confirmed the in vivo efficacy of 
p
y
anti-mouse PD-1 antibody as a monotherapy, as well as in combination with chemotherapy, in
y
syngeneic mouse tumor models.15
Current evidence reveals an association between mutational tumor burden and tumor 
immunogenicity.16,17,18 In order to grow, antigenic tumors must develop mechanisms that enable 
g
y
g
,
g
p
them to evade immune-mediated destruction through a process termed immunoediting.19 However, 
g
p
while mutational load represents a predictive factor for ICI therapy,20,21
g
,
its predictive power is 
p
p
py,
p
p
modest; rather, it seems associated with the presence of specific neoantigen-generating 
;
mutations.16
,
p
p
g
g
g
This observation, supported by both preclinical- and clinical-evidence, suggests that 
,
pp
y
p
,
gg
a qualitative neoantigen-directed immunotherapy holds great potential. New therapeutic 
q
g
py
g
p
p
modalities in this category should ideally meet 2 critical criteria: 1) display tumor-specific antigens 
g
y
y
)
p y
p
g
and 2) induce an inflamed tumor microenvironment. Furthermore, the capacity of such therapeutic 
)
,
p
y
p
modalities may result in an extended patient population of responders and potentially increase the 
y
overall efficacy of ICIs. 
CyPep-1 is an engineered synthetic peptide with oncolytic properties. It consists of 27 amino acids 
y
p
g
y
p p
y
p
p
and specifically targets tumor cells due to their altered electrochemical properties while leaving
p
y
g
p
p
g
normal cells intact. CyPep-1 modulates the tumor microenvironment by increasing the presence 
y
p
y
g
p
of CD8+ T cells and potentiates the effects of ICIs. CyPep-1 is an amorphous white to off-white 
p
y
p
p
powder, with no crystalline or polymorphic forms identified to date. The molecular mass of 
p
,
y
p y
p
CyPep-1, as determined based on a combination of electrospray ionization-mass spectrometry and
f
y
p
,
y
p
,
amino acid analysis, is 3492.2 Daltons. 
1.1
Preclinical 
Clinical Data Summary 
1.1.1
Preclinical Studies With CyPep-1 
In animal studies, CyPep-1 was administered intravenously (IV) (0.5 mg/kg to 20 mg/kg in rats 
,
y
p
y (
) (
g g
g g
and 0.1 mg/kg to 7 mg/kg in dogs) or topically (formulated as 1.0% cream). For all Good
g g
g g
g )
p
y (
)
Laboratory Practice studies, the test products contained CyPep-1 alone or with compendial 

Cytovation ASA 
Clinical Study Protocol CYP003 
Confidential & Proprietary 
Page 28 of 102 
Version 4.0, 23 November 2022 
excipients that have been previously approved for use in pharmaceutical products. The following 
conclusions were derived from the toxicity studies of IV CyPep-1: 
Systemic administration of CyPep-1 was well tolerated in rats at levels of up to 10 mg/kg upon 
single IV bolus injection, and at levels of 3 mg/kg/day upon repeat (7-day) IV bolus 
administration (Study 506066); 
At a dose of 0.5 mg/kg/day, systemic administration of CyPep-1 was well tolerated for 4 weeks 
in rats, with no clinical signs observed and minimal pathology findings (Study 506092);  
There were no CyPep-1-related effects on body weight, body temperature, pupil size 
(Study 614721), respiratory rate, tidal volume, and minute volume (Study 614716) at single 
IV doses of 0.5, 1, or 3 mg/kg; 
CyPep-1 is not mutagenic in a standard battery of in vitro and in vivo genotoxicity tests 
(Studies 01027002, 01027003); 
No cardiotoxicity was observed upon CyPep-1 administration (Study 614700); 
Upon subcutaneous administration of 3 mg/kg in rats, CyPep-1 could not be detected in 
plasma;  
Combined single dose (maximum tolerated dose [MTD]) and dose range finding (DRF) studies 
in rats demonstrated good tolerability up to 10 mg/kg as a single dose and up to 3 mg/kg/day 
on a repeated dose basis. Similarly, MTD and DRF studies were performed in dogs. Due to the 
clinical findings observed in the male at 7 mg/kg, this dose was considered to be above the 
MTD level. At doses up to 5 mg/kg/day, red skin and gums were often evident immediately 
after dosing during the MTD phase and in the female during the DRF phase; and 
Regarding cardiotoxicity testing, an in vivo cardiotoxicity study was performed in telemetered 
dogs to evaluate effects of CyPep-1 on arterial blood pressure, heart rate, lead II 
electrocardiogram (ECG) findings, and body temperature following a single IV administration. 
No clinical signs noted in any of the dogs were attributed to the administration of CyPep-1, 
and body weight was unaffected by treatment. Based on these results, the no observed adverse 
effect level was considered to be 1 mg/kg. 
Of the non-clinical development programs completed to date, the safety profile of CyPep-1 has 
been established. The non-clinical program supports the short-term and longer-term use of 
CyPep-1 in clinical trials. 
1.1.2
Clinical Studies With CyPep-1 
Humans have been exposed to CyPep-1 in a topical formulation. As IT formulation, CyPep-1 has 
been assessed in a dose escalation Phase 1 study (as monotherapy in a first-in-human Phase 1/2a 
clinical study [CICILIA] and a combination with pembrolizumab). The CICILIA study is an 
open-label, dose escalation, and dose expansion Phase 1/2a study of IT CyPep-1 and was initiated 
in patients with advanced solid cancers for whom no treatment options exist. The CICILIA study 
was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary 
anti-tumor efficacy of CyPep-1 when administered directly into malignant tumors, either in 
monotherapy or in combination with the anti-PD-1 antibody, pembrolizumab. Additionally, the 
immuno-modulatory effects of CyPep-1 are planned to be assessed in exploratory analyses, alone 
and in combination with the anti-PD-1 antibody. 
excipients that have been previously approved for use in pharmaceutical products. The following
p
p
y pp
p
conclusions were derived from the toxicity studies of IV CyPep-1: 
Systemic administration of CyPep-1 was well tolerated in rats at levels of up to 10 mg/kg upon
t
y
y
p
p
g g p
single IV bolus injection, and at levels of 3 mg/kg/day upon repeat (7-day) IV bolus
f
g
j
,
administration (Study 506066); 
At a dose of 0.5 mg/kg/day, systemic administration of CyPep-1 was well tolerated for 4 weeks 
g g
y, y
y
p
in rats, with no clinical signs observed and minimal pathology findings (Study 506092); 
There were no CyPep-1-related effects on body weight, body temperature, pupil size 
y
p
y
g ,
y
p
, p p
(Study 614721), respiratory rate, tidal volume, and minute 
r
volume (Study 614716) at single 
(
y
),
p
y
IV doses of 0.5, 1, or 3 mg/kg; 
CyPep-1 is not mutagenic in a standard battery of in vitro and in vivo genotoxicity tests 
r
y
p
g
(Studies 01027002, 01027003);
No cardiotoxicity was observed upon CyPep-1 administration (Study 614700); 
Upon subcutaneous administration of 3 mg/kg in rats, CyPep-1 could not be detected in 
p
plasma; 
Combined single dose (maximum tolerated dose [MTD]) and dose range finding (DRF) studies 
g
(
[
])
g
g (
)
in rats demonstrated good tolerability up to 10 mg/kg as a single dose and up to 3 mg/kg/day 
g
y p
g g
g
p
g g
y
on a repeated dose basis. Similarly, MTD and DRF studies were performed in dogs. Due to the
p
y,
p
g
clinical findings observed in the male at 7 mg/kg, this dose was considered to be above the 
g
g g,
MTD level. At doses up to 5 mg/kg/day, red skin and gums were often evident immediately 
p
g g
y,
g
after dosing during the MTD phase and in the female during the DRF phase; and 
Regarding cardiotoxicity testing, an in vivo cardiotoxicity study was performed in telemetered 
g
g
y
g,
y
y
p
dogs to evaluate effects of CyPep-1 on arterial blood pressure, heart rate, lead II 
g
y
p
p
,
,
electrocardiogram (ECG) findings, and body temperature following a single IV administration. 
g
(
)
g ,
y
p
g
g
No clinical signs noted in any of the dogs were attributed to the administration of CyPep-1, 
g
y
g
y
p
,
and body weight was unaffected by treatment. Based on these results, the no observed adverse
y
g
y
effect level was considered to be 1 mg/kg. 
-1 has 
Of the non-clinical development programs completed to date, the safety profile of CyPep
been established. The non-clinical program supports the short-term and longer-term use of 
p
p
g
p
,
y p
y
p
CyPep-1 in clinical trials. 
1.1.2
2022 
Clinical Studies With CyPep-1 
Humans have been exposed to CyPep-1 in a topical formulation. As IT formulation, CyPep-1 has 
p
y
p
p
,
y
p
been assessed in a dose escalation Phase 1 study (as monotherapy in a first-in-human Phase 1/2a 
y (
py
clinical study [CICILIA] and a combination with pembrolizumab). The CICILIA study is an 
y [
]
p
)
y
open-label, dose escalation, and dose expansion Phase 1/2a study of IT CyPep-1 and was initiated 
p
,
,
p
y
y
p
in patients with advanced solid cancers for whom no treatment opt
d
ions exist. The CICILIA study 
p
p
y
was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary 
g
y,
y, p
(
),
p
y
anti-tumor efficacy of CyPep-1 when administered directly into malignant tumors, either in
d
y
y
p
y
g
,
monotherapy or in combination with the anti-PD-1 antibody, pembrolizumab. Additionally, the 
py
y, p
y,
immuno-modulatory effects of CyPep-1 are planned to be assessed in exploratory analyses, alone 
y
y
p
p
and in combination with the anti-PD-1 antibody. 

Cytovation ASA 
Clinical Study Protocol CYP003 
Confidential & Proprietary 
Page 29 of 102 
Version 4.0, 23 November 2022 
In Phase 1 (dose escalation) of the CICILIA trial, 3 dose cohorts of 3 subjects each received 
CyPep-1 IT at different concentrations and volumes (depending on tumor size), ie, 0.5 mg/mL (up 
to 2 mg/day), 2 mg/mL (up to 8 mg/day), and 5 mg/mL (up to 20 mg/day), respectively.  
Preliminary efficacy data from the CICILIA study indicate that decreases in the size of tumors 
were observed in 1 subject (lesions 2, 3, and 4) and in another subject after the first CyPep-1 
administration, whereas the third subject had a stable tumor size. Based on these data, specifically 
the lack of systemic or local reactions to injection, and the lack of serious adverse events (SAEs) 
related to CyPep-1, the Dose Escalation Committee decided to initiate administration of CyPep-1 
in Cohort 2. 
The PK profile was evaluated as part of the CICILIA trial as a secondary endpoint. Serum samples 
from all subjects that were part of the dose escalation Phase 1 were analyzed. In total, 3 patients 
were included in Cohort 1 (0.5 mg/mL), 5 patients in Cohort 2 (2 mg/mL) and 3 patients in 
Cohort 3 (5 mg/mL). Dosing was on Day 1 in Weeks 1, 3, and 5 and PK was collected after the 
first dose (Day 1), up to 4 hours after drug administration. Blood samples for PK determination 
were drawn prior to start of administration, 15 and 30 minutes, and 1, 2, and 4 hours after drug 
administration. 
The individual time-serum profiles for CyPep-1 are shown in Figure 1. A majority of all blood 
samples had concentrations of CyPep-1 below limit of quantification (LOQ). One subject in 
Cohort 2 had no pre-dose sample collected, but was treated as being below the LOQ. 
 
 
In Phase 1 (dose escalation) of the CICILIA trial, 3 dose cohorts of 3 subjects each received 
(
)
,
j
CyPep-1 IT at different concentrations and volumes (depending on tumor size), ie, 0.5 mg/mL (up 
y
p
(
p
g
),
,
to 2 mg/day), 2 mg/mL (up to 8 mg/day), and 5 mg/mL (up to 20 mg/day), respectively. 
Preliminary efficacy data from the CICILIA study indicate that decreases in the size of tumors 
y
y
y
were observed in 1 subject (lesions 2, 3, and 4) and in another subject after the first CyPep-1
j
(
,
,
)
j
y
p
administration, whereas the third subject had a stable tumor size. Based on these data, specifically 
,
j
, p
y
the lack of systemic or local reactions to injection, and the lack of serious adverse events (SAEs) 
y
j
,
(
)
related to CyPep-1, the Dose Escalation Committee decided to initiate administration of CyPep-1 
y
in Cohort 2.
The PK profile was evaluated as part of the CICILIA trial as a secondary endpoint. Serum samples 
p
p
y
p
p
from all subjects that were part of the dose escalation Phase 1 were analyzed. In total, 3 patients 
j
p
y
,
p
were included in Cohort 1 (0.5 mg/mL), 5 patients in Cohort 2 (2 mg/mL) and 3 patients in 
(
g
),
p
(
g
)
p
Cohort 3 (5 mg/mL). Dosing was on Day 1 in Weeks 1, 3, and 5 and PK was collected after the 
(
g
)
g
y
,
,
first dose (Day 1), up to 4 hours after drug administration. Blood samples for PK determination 
(
y
),
p
g
p
were drawn prior to start of administration, 15 and 30 minutes, and 1, 2, and 4 hours after drug 
p
administration. 
The individual time-serum profiles for CyPep-1 are shown
r
in Figure 1. A majority of all blood 
p
y
p
g
j
y
samples had concentrations of CyPep-1 below limit of quantification (LOQ). One subject in
p
y
p
q
(
Q)
Cohort 2 had no pre-dose sample collected, but was treated as being below the LOQ. 
t

Cytovation ASA 
Clinical Study Protocol CYP003 
Confidential & Proprietary 
Page 30 of 102 
Version 4.0, 23 November 2022 
Table 1. 
Individual CyPep-1 Concentrations (ng/mL) by Time (CICILIA Study) 
Cohort 
Subject 
Dose 
Scheduled Time (h) 
Pre-dose 
15 min 
30 min 
1 h 
2 h 
4 h 
1 
 
 
 
 
 
 
 
01-004 
1 
<10 
<10 
<10 
<10 
<10 
<10 
03-001 
1 
<10 
<10 
<10 
<10 
<10 
<10 
02-003 
1 
<10 
<10 
<10 
<10 
<10 
<10 
2 
 
 
 
 
 
 
 
01-005 
1 
<10 
<10 
<10 
<10 
<10 
<10 
01-006 
1 
<10 
11.8 
<10 
<10 
<10 
<10 
02-004 
1 
- 
33.7 
<10 
<10 
<10 
<10 
02-005 
1 
<10 
14.3 
<10 
<10 
<10 
<10 
05-001 
1 
<10 
226 
72.7 
24.1 
13.4 
10.2 
3 
 
 
 
 
 
 
 
01-007 
1 
<10 
19.7 
<10 
<10 
<10 
<10 
02-006 
1 
<10 
164 
88.3 
15.9 
11.7 
<10 
02-007 
1 
<10 
<10 
<10 
<10 
<10 
<10 
h = hour(s); min = minute(s). 
Source: Investigator¶s Brochure for CyPep-1
Table 2. 
Individually Computed Single-Dose Pharmacokinetic Parameters Based on 
CyPep-1 Concentrations (CICILIA Study) 
Cohort 
Subject 
Dose 
(mg/mL) 
Cmax
(ng/mL) 
Tmax
(h) 
AUC0-inf
(ng*h/mL) 
AUC0-t
(ng*h/mL) 
AUC0-4
(ng*h/mL) 
MRT 
t½(h) 
AUC 
extr.(%) 
2 
 
 
 
 
 
 
 
 
 
01-006 
2 
11.8 
0.22 
 
 
 
 
 
 
02-004 
2 
33.7 
0.45 
 
 
 
 
 
 
02-005 
2 
14.3 
0.50 
 
 
 
 
 
 
05-001 
2 
226.0 
0.25 
170.6 
132.1 
132.1 
2.50 
2.61 
22.5 
3 
 
 
 
 
 
 
 
 
 
01-007 
2 
19.7 
0.25 
 
 
 
 
 
 
02-006 
2 
164.0 
0.25 
105.1 
95.6 
104.3 
0.76 
0.56 
9.0 
AUC0-4 = area under the curve from time 0 to 4 hours post dose; AUC0-inf = area under the curve from time 0 to infinity; 
AUC0-t = area under the curve from time 0 to end of the dosing period; Cmax = peak plasma concentration; extr = extrapolated; 
h = hour(s); MRT = mean residence time; t½ = elimination half-life; Tmax = time to reach peak plasma concentration. 
Source: Investigator¶s Brochure for CyPep-1
Table 1. 
Individual CyPep-1 Concentrations (ng/mL) by Time (CICILIA Study)
Scheduled Time (h)
Cohort 
Subject 
Dose 
Pre-dose 
15 min 
30 min 
)
1 h 
2 h 
4 h 
1 
01-004 
1 
<10 
<10 
<10 
<10 
<10 
<10 
03-001 
1 
<10 
<10 
<10 
<10 
<10 
<10 
02-003 
1 
<10 
<10 
<10 
<10 
<10 
<10 
2 
01-005 
1 
<10 
<10 
<10 
<10 
<10 
<10 
01-006 
1 
<10 
11.8 
<10 
<10 
<10 
<10 
02-004 
1 
- 
33.7 
<10 
<10 
<10 
<10 
02-005 
1 
<10 
14.3 
<10 
<10 
<10 
<10 
05-001 
1 
<10 
226 
72.7 
24.1 
13.4 
10.2 
3 
01-007 
1 
<10 
19.7 
<10 
<10 
<10 
<10 
02-006 
1 
<10 
164 
88.3 
15.9 
11.7 
<10 
02-007 
1 
<10 
<10 
<10 
<10 
<10 
<10 
h = hour(s); min = minute(s). 
( );
( )
Source: Investigator¶s Brochure for CyPep-1
Table 2. 
Individually Computed Single-Dose Pharmacokinetic Parameters Based on
y
p
g
CyPep-1 Concentrations (CICILIA Study) 
Cohort 
Dose 
Cmax
Tmax
AUC0-
AUC0-t
AUC0-
AUC 
inf
t
4
Subject 
(mg/mL) 
(ng/mL) 
(h) 
(ng*h/mL) 
(ng*h/mL) 
(ng*h/mL) 
MRT 
t (h) 
extr.(%) 
½
2 
01-006 
2 
11.8 
0.22 
02-004 
2 
33.7 
0.45 
02-005 
2 
14.3 
0.50 
05-001 
2 
226.0 
0.25 
170.6 
132.1 
132.1 
2.50 
2.61 
22.5 
3 
01-007 
2 
19.7 
0.25 
02-006 
2 
164.0 
0.25 
105.1 
95.6 
104.3 
0.76 
0.56 
9.0 
AUC0-4 = area under the curve from time 0 to 4 hours post dose; AUC0-i
= area under the curve from time 0 to infinity;
4
inf
p
;
y;
AUC0- = area under the curve from time 0 to end of the dosing period; Cmax = peak plasma concentration; extr = extrapolated; 
t
g p
;
p
p
;
h = hour(s); MRT = mean residence time; t = elimination half-life; Tmax = time to reach peak plasma concentration. 
t½
( );
;
Source: Investigator¶s Brochure for CyPep-1

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Figure 1. Individual Time-Serum Profiles for CyPep-1 (CICILIA Study) 
be 
computed in only 2 instances, for 1 subject in Cohort 2 and 1 subject in Cohort 3. For 4 additional 
subjects (3 in Cohort 2 and 1 in Cohort 3) at least 1 sample was quantifiable enabling peak plasma 
concentration (Cmax) and time to reach Cmax (Tmax) to be computed as sole PK parameters. 
Descriptive statistics of the computed PK parameters by cohort is provided in Table 3. 
Table 3. 
Descriptive Statistics of Computed Pharmacokinetic Parameters by Cohort 
(CICILIA Study) 
PK Parameter 
Descriptive Statistics 
Cohort 1 
Cohort 2 
Cohort 3 
Cmax (ng/mL) 
 
 
 
n 
0 
4 
2 
GM 
 
33.67 
56.84 
CV 
 
227 
291 
Range 
 
11.8-226.0 
19.7-164.0 
Tmax (h) 
 
 
 
n 
0 
4 
2 
GM 
 
0.35 
0.25 
CV 
 
0.14 
0.00 
Range 
 
0.2-0.5 
0.3-0.3 
Cmax = peak plasma concentration; CV = coefficient of variation; GM = geometric mean; Tmax = time to reach peak plasma 
concentration. 
Source: Investigator¶s Brochure for CyPep-1
p
CICILIA Study) 
PK Parameter 
Descriptive Statistics
Cohort 1 
Cohort 2 
Cohort 3 
p
Cmax (ng/mL) 
n 
0 
4 
2 
GM 
33.67 
56.84 
CV 
227 
291 
Range 
11.8-226.0 
19.7-164.0 
g
Tmax (h) 
n 
0 
4 
2 
GM 
0.35 
0.25 
CV 
0.14 
0.00 
Range 
0.2-0.5 
0.3-0.3 
Cmax = peak plasma concentration; CV = coefficient of variation; GM = geometric mean; Tmax = time to reach peak plasma 
p
p
concentration. 
Source: Investigator¶s Brochure for CyPep

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To date in the CICILIA study, the most frequently reported treatment-emergent adverse event 
(TEAE) was ³injection site pain´ and occurred in all 3 dose cohorts. No fatal TEAE or 
SAE/Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported. Additionally, 
no TEAE leading to CyPep-1 discontinuation was reported; see Table 4 which shows data from 
the Safety Report of the CICILIA study part I (dose escalation). 
The most common CyPep-1-related adverse event (AE) was ³injection site pain´ and was reported 
in Cohorts 2 and 3.  
Table 4. 
Cumulative Treatment-Emergent Adverse Events and CyPep-1-Related 
Treatment-Emergent Adverse Events by Preferred Term (CICILIA Study) 
Cohort 
AE PT  
Grade 1 
(n events) 
Grade 2 (n 
events) 
Grade 3/4 
(n events) 
All Grades 
(n events) 
SAE/SUSARS 
Cumulative TEAEs per PT 
1 
Constipation 
3 
0 
0 
3 
0 
1 
Injection site pain 
2 
0 
0 
2 
0 
2 
Anaemia 
0 
1 
1 
2 
0 
2 
Cough 
1 
1 
0 
2 
0 
2 
Fatigue 
1 
1 
0 
2 
0 
2 
Injection site pain 
5 
1 
0 
6 
0 
2 
Nausea 
2 
0 
0 
2 
0 
2 
Cancer pain 
1 
2 
0 
3 
0 
2 
Urinary tract 
infection 
0 
2 
0 
2 
0 
2 
Vomiting 
1 
0 
1 
2 
0 
3 
Cancer pain 
7 
6 
1 
14 
0 
3 
Constipation 
3 
1 
0 
4 
0 
3 
Fatigue 
2 
0 
0 
2 
0 
3 
Injection site pain 
15 
1 
0 
16 
0 
Cumulative CyPep-1-related TEAEs per PT 
3 
Injection site pain 
11 
1 
0 
12 
0 
2 
Injection site pain 
5 
1 
0 
6 
0 
2 
Fatigue 
0 
1 
0 
1 
0 
1 
Pyrexia 
1 
0 
0 
1 
0 
2 
Nausea 
1 
0 
0 
1 
0 
2 
Rash macular 
1 
0 
0 
1 
0 
2 
Vomiting 
1 
0 
0 
1 
0 
3 
Injection site 
oedema 
1 
0 
0 
1 
0 
3 
Pain in extremity 
1 
0 
0 
1 
0 
3 
Platelet count 
decreased 
1 
0 
0 
1 
0 
3 
Skin wound 
1 
0 
0 
1 
0 
3 
Vitiligo 
1 
0 
0 
1 
0 
AE = adverse event; n = number of subjects; PT = preferred term; SAE = serious adverse event; SUSAR = Suspected Unexpected 
Serious Adverse Reaction; TEAE = treatment-emergent adverse event. 
Source: Investigator¶s Brochure for CyPep-1 
Analysis of the reported TEAEs across the dose cohorts showed no increase in the number of 
TEAEs per subject in the higher dose levels; see Table 5. 

Cytovation ASA 
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Version 4.0, 23 November 2022 
Table 5. 
Frequency of Reported Treatment-Emergent Adverse Events per Dose Cohort 
(CICILIA Study) 
Cohort 1 (n=3) 
Cohort 2 (n=5) 
Cohort 3 (n=6) 
Relatedness 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Not related 
TEAE 
10 
2 
7 
12 
9 
5 
20 
9 
3 
Related TEAE 
1 
0 
0 
8 
2 
0 
16 
1 
0 
n = number of subjects; TEAE = treatment-emergent adverse event. 
Source: Investigator¶s Brochure for CyPep-1 
Additionally, CyPep-1 is currently being evaluated in a randomized, placebo-controlled, 
double-blind, single center Phase 1 study as topical formulation administered to subjects with 
cutaneous warts (Study CHDR1803). 
1.2
Rationale 
Cytovation ASA is currently developing CyPep-1 for the treatment of advanced solid cancers.  
CyPep-1 is a synthetic linear 27-amino acid peptide that induces tumor cell death, resulting in the 
release of tumor antigens, and potentially induces a tumor-specific immune response by in situ 
immunization. CyPep-1 has been shown to selectively target tumor cell membranes based on their 
altered molecular composition, which in turn leads to lysis of tumor cells by removal of the cell 
membrane. This mode of action of CyPep-1 induces tumor cell death resulting in the release of 
tumor antigens, and potentially induces a tumor-specific immune response by in situ 
immunization. Conceptually, clinical proof-of-concept of this strategy has been established by 
lytic viruses, and preliminary evidence indicates that oncolytic treatment can induce systemic 
anti-tumoral responses.22 Due to its unique antigen-exposing properties, CyPep-1 could be a more 
potent and less toxic oncolytic therapy. Preclinical toxicology studies have shown a favorable 
safety profile and potent anti-tumor activity of CyPep-1 in several tumor models. CyPep-1 was 
shown to modulate the tumor microenvironment by increasing the presence of CD8+ T cells and 
by potentiating the effects of ICIs.15 As such, the hypothesis is that IT injection with CyPep-1 leads 
to transformation of immunological ³cold´ ICI treatment-resistant tumors into ³hot´ 
immunological active tumors that can be successfully treated with immune-modulating agents. In 
addition, CyPep-1 offers attractive pharmacological properties such as long shelf life, easy 
scalability, and batch-to-batch consistency. As such, CyPep-1 may represent a unique 
³tumor-agnostic´ compound bolstering the effect of established immunotherapy across multiple 
tumor types.  
Preclinical studies show that CyPep-1 can synergize with anti-PD-1 antibody treatment in terms 
of decreased tumor volumes and prolonged Overall Survival (OS), highlighting the possible 
clinical utility of CyPep-1 in the combination setting with ICIs. 
CyPep-1 specifically targets tumor cells due to the altered electrochemical properties within the 
tumor and leaves normal cells intact. IT administration allows optimal pharmacological conditions, 
by maximizing tumor exposure to the drug while minimizing systemic exposure and toxicity. 
Pembrolizumab (MK-3475) is a potent humanized immunoglobulin G4 monoclonal antibody with 
high specificity of binding to PD-1, thus inhibiting its interaction with PD-L1 and programmed 
cell death ligand 2. Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an IV immunotherapy for advanced malignancies. Keytruda®
Rationale 
Cytovation ASA is currently developing CyPep-1 for the treatment of advanced solid cancers. 
CyPep-1 is a synthetic linear 27-amino acid peptide that induces tumor cell death, resulting in the 
y
p
y
p p
,
g
release of tumor antigens, and potentially induces a tumor-specific immune response by in situ 
g
,
p
y
p
p
y
immunization. CyPep-1 has been shown to selectively target tumor cell membranes based on their 
y
p
y
g
altered molecular composition, which in turn leads to lysis of tumor cells by removal of the cell 
p
,
y
y
membrane. This mode of action of CyPep-1 induces tumor cell death resulting in the release of 
y
p
g
tumor antigens, and potentially induces a tumor-specific immune response by in situ
g
,
p
y
p
p
y
immunization. Conceptually, clinical proof-of-concept of this strategy has been established by 
p
y,
p
p
gy
y
lytic viruses, and preliminary evidence indicates that oncolytic treatment can induce systemic 
y
,
p
anti-tumoral responses.22
y
y
y
Due to its unique antigen-exposing properties, CyPep-1 could be a more
p
q
g
p
g p
p
,
y
p
potent and less toxic oncolytic therapy. Preclinical toxicology studies have shown a favorable 
p
y
py
gy
safety profile and potent anti-tumor activity of CyPep-1 in several tumor models. CyPep-1 was
t
y p
p
y
y
p
y
p
shown to modulate the tumor microenvironment by increasing the presence of CD8+ T cells and 
by potentiating the effects of ICIs.15
y
g
p
As such, the hypothesis is that IT injection with CyPep-1 leads 
y p
g
,
yp
j
y
p
to transformation of immunological ³cold´ ICI treatment-resistant tumors into ³hot´
g
immunological active tumors that can be successfully treated with immune-modulating agents. In 
g
y
g g
addition, CyPep-1 offers attractive pharmacological properties such as long shelf life, easy
,
y
p
p
g
p
p
g
,
y
scalability, and batch-to-batch consistency. As such, CyPep-1 may represent a unique 
y,
y
,
y
p
y
p
q
³tumor-agnostic´ compound bolstering the effect of established immunotherapy across multiple
g
tumor types. 
Preclinical studies show that CyPep-1 can synergize with anti-PD-1 antibody treatment in terms
y
p
y
g
y
of decreased tumor volumes and prolonged Overall Survival (OS), highlighting the possible
p
g
clinical utility of CyPep-1 in the combination setting with ICIs. 
CyPep-1 specifically targets tumor cells due to the altered electrochemical properties within the 
y
p
p
y
g
p
p
tumor and leaves normal cells intact. IT administration allows optimal pharmacological conditions, 
p
p
g
by maximizing tumor exposure to the drug while minimizing systemic exposure and toxicity. 
Pembrolizumab (MK-3475) is a potent humanized immunoglobulin G4 monoclonal antibody with
(
)
p
g
y
high specificity of binding to PD-1, thus inhibiting its interaction with PD-L1 and programmed 
g
p
y
g
,
g
p
g
cell death ligand 2. Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
g
p
, p
g
y
p
receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile 
p
g
y
p
p
y p
and is in clinical development as an IV immunotherapy for advanced malignancies. Keytruda

Cytovation ASA 
Clinical Study Protocol CYP003 
Confidential & Proprietary 
Page 34 of 102 
Version 4.0, 23 November 2022 
(pembrolizumab) is indicated for the treatment of patients across several indications. See the 
Investigator¶s Brochure (IB) for detailed background information on pembrolizumab.23  
Currently, over 20 patients have been dosed with CyPep-1. The safety profile has been very 
favorable when compared to other oncology drugs. Additional CICILIA safety data is on file with 
the Sponsor and is consistent with this clinical safety profile. There were no clinical safety events 
(defined as any events falling under the definition of dose-limiting toxicity [DLT]) reported. 
One TEAE was determined to be serious, but it was not related to the treatment (dyspnea due to 
lung infection). None of the TEAEs resulted in death or discontinuation of study treatment. As 
such, these results are in line with the published literature indicating that the IT administration is 
safe and well tolerated. 
CICILIA Arm B evaluated the combination of 20 mg of CyPep-1 with pembrolizumab. The first 
3 patients recruited completed the DLT observation period defined in the protocol and their safety 
data was assessed by the Dose Escalation Committee (DEC) on 4 March 2022. No DLTs, no SAEs, 
and no treatment discontinuations due to TEAEs were observed. No AEs related to pembrolizumab 
were reported. The most common AE related to CyPep-1 was pain at the injection site, starting 
during or after the injection and lasting a few hours. DEC recommendation was to proceed to 
enrollment of the remaining patients. Since then, and as of 20 May 2022, 8 additional patients have 
been recruited in Arm B. In this expansion cohort, 1 SUSAR has been observed. The SUSAR 
patient was an 80 year old woman with an anaplastic thyroid carcinoma previously treated with 
thyroidectomy, radiation therapy, and 3 lines of systemic therapy. Two days after the intra-tumoral 
injection on the local recurrent neck lesion, the patient was admitted to the hospital due to Grade 2 
facial edema involving the lip and left hemiface, with concomitant Grade 2 site injection erythema. 
Both symptoms resolved in less than 24 hours after treatment with histamines. The causality 
assessment by Investigator and Sponsor was probably related to CyPep-1 and/or IT administration 
and unrelated to pembrolizumab. 
This Phase 1b/2a study will assess the efficacy, safety, and pharmacodynamics of CyPep-1 when 
administered directly into measurable tumor lesions in combination with the anti-PD-1 antibody 
pembrolizumab. Additionally, the study will assess anti-tumor effects of CyPep-1 on injected 
lesions and non-injected target lesions identified at baseline, as well as local and systemic 
immunological effects of CyPep-1 in combination with pembrolizumab. 
1.3
Risk/Benefit 
1.3.1
Potential Risks 
Based on preclinical experience and available clinical data from the ongoing Phase 1/2a CICILIA 
study, there are no specific adverse reactions to be inferred as ³expected´ at the 20 mg every 
2 weeks (Q2W) dose level of CyPep-1. 
Nevertheless, CyPep-1 is a soluble synthetic peptide with the potential risk of inducing allergic 
reactions. Possible AEs associated with an allergic reaction include fever, chills, headache, 
weakness, nausea, vomiting, diarrhea, low blood pressure, respiratory symptoms, and rashes. 
Additionally, since the mode of action of CyPep-1 includes potential stimulation of the immune 
response, there is a likelihood of immune-related AEs (irAEs). Generally, such AEs have been 
observed after specific blocking of inhibitory receptors expressed on T cells (eg, PD-1) rather than 
after induction of tumor-specific immune responses. If CyPep-1 elicits a particularly strong T cell 
(pembrolizumab) is indicated for the treatment of patients across several indications. See the 
(p
)
p
Investigator¶s Brochure (IB) for detailed background information on pembrolizumab.
d
23
Currently, over 20 patients have been dosed with CyPep-1. The safety profile has been very 
y,
p
y
p
y p
y
favorable when compared to other oncology drugs. Additional CICILIA safety data is on file with 
p
gy
g
y
the Sponsor and is consistent with this clinical safety profile. There were no clinical safety events 
p
y p
y
(defined as any events falling under the definition of dose-limiting toxicity [DLT]) reported. 
(
y
g
g
y [
])
p
One TEAE was determined to be serious, but it was not related to the treatment (dyspnea due to 
,
( y p
lung infection). None of the TEAEs resulted in death or discontinuation of study treatment. As 
g
)
y
such, these results are in line with the published literature indicating that the IT administration is 
,
safe and well tolerated.
CICILIA Arm B evaluated the combination of 20 mg of CyPep-1 with pembrolizumab. The first 
g
y
p
p
3 patients recruited completed the DLT observation period defined in the protocol and their safety 
p
p
p
p
y
data was assessed by the Dose Escalation Committee (DEC) on 4 March 2022. No DLTs, no SAEs, 
y
(
)
,
,
and no treatment discontinuations due to TEAEs were observed. No AEs related to pembrolizumab
p
were reported. The most common AE related to CyPep-1 was pain at the injection site, starting
p
y
p
p
j
,
g
during or after the injection and lasting a few hours. DEC recommendation was to proceed to 
g
j
g
p
enrollment of the remaining patients. Since then, and as of 20 May 2022, 8 additional patients have
g p
,
y
,
p
been recruited in Arm B. In this expansion cohort, 1 SUSAR has been observed. The SUSAR 
p
,
patient was an 80 year old woman with an anaplastic thyroid carcinoma previously treated with 
p
y
p
y
p
y
thyroidectomy, radiation therapy, and 3 lines of systemic therapy. Two days after the intra-tumoral 
y
y,
py,
y
py
y
injection on the local recurrent neck lesion, the patient was admitted to the hospital due to Grade 2 
j
,
p
p
facial edema involving the lip and left hemiface, with concomitant Grade 2 site injection erythema.
g
p
,
j
y
Both symptoms resolved in less than 24 hours after treatment with hist
f
amines. The causality 
y p
y
assessment by Investigator and Sponsor was probably related to CyPep-1 and/or IT administration
y
g
p
and unrelated to pembrolizumab. 
Nevertheless, CyPep-1 is a soluble synthetic peptide with the potential risk of inducing allergic 
,
y
p
y
p p
p
g
g
reactions. Possible AEs associated with an allergic reaction include fever, chills, headache, 
g
,
,
,
weakness, nausea, vomiting, diarrhea, low blood pressure, respiratory symptoms, and rashes. 
,
,
g,
,
p
,
p
y
y p
,
Additionally, since the mode of action of CyPep-1 includes potential stimulation of the immune 
y,
y
p
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response, there is a likelihood of immune-related AEs (irAEs). Generally, such AEs have been
f
p
,
(
)
y,
observed after specific blocking of inhibitory receptors expressed on T cells (eg, PD-1) rather than
p
g
y
p
p
( g,
)
after induction of tumor-specific immune responses. If CyPep-1 elicits a particularly strong T cell 

Cytovation ASA 
Clinical Study Protocol CYP003 
Confidential & Proprietary 
Page 35 of 102 
Version 4.0, 23 November 2022 
immune response in a few patients predisposed to develop autoimmunity, irAEs may nonetheless 
be observed.  
In addition to potential risks related to administration of CyPep-1 (eg, leakage into circulation), 
there are also procedural risks related to blood sampling, other possible subcutaneous injections, 
and diagnostic procedures. Blood sampling and subcutaneous injections may cause pain, bleeding, 
bruising, and/or infections at the site of cannula insertion. Rare complications due to blood 
sampling are syncope, thrombophlebitis, and accidental punctures of an artery or nerve. 
Based on an acceptable tolerability profile and manageable AEs, as well as preliminary PK results 
and efficacy signals, further dose assessment of CyPep-1 (20 mg Q2W) in combination with 
pembrolizumab 400 mg every 6 weeks (Q6W) will be explored in a DLT Phase 1b portion with 
confirmation of a recommended dose for Phase 2. These data will underpin further assessment of 
the safety, tolerability, and preliminary efficacy of CyPep-1 in combination pembrolizumab. 
The risks of pembrolizumab administration are detailed in the IB.23 Pembrolizumab has been 
documented to cause immune-related adverse reactions, for which a series of measures are 
recommended (see Section 5.5.3.3). 
1.3.2
Benefit 
The efficacy and safety data, together with the pharmacodynamic data obtained from this study, 
will help design subsequent clinical studies in the target populations. Treatment of patients with 
CyPep-1 in combination with pembrolizumab is expected to result in improvement or stabilization 
of the disease state of the patients. 
1.4
Coronavirus Disease 2019 Impacts 
In March 2020, the Coronavirus Disease 2019 (COVID-19), caused by infection with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), was characterized as a pandemic by the 
World Health Organization. The COVID-19 pandemic has impacted clinical studies worldwide 
due to quarantines, study site closures, travel limitations, diversion of resources, and/or general 
interruptions in study-related procedures.  
The impacts of the COVID-19 pandemic on the outcomes of this study, including any protocol 
deviations that result from COVID-19 illness and/or COVID-19 control measures, will be 
discussed in the Clinical Study Report (CSR). 
immune response in a few patients predisposed to develop autoimmunity, irAEs may nonetheless 
p
be observed. 
In addition to potential risks related to administration of CyPep-1 (eg, leakage into circulation),
p
y
p
( g,
g
),
there are also procedural risks related to blood sampling, other possible subcutaneous injections, 
p
p
g,
p
j
,
and diagnostic procedures. Blood sampling and subcutaneous injections may cause pain, bleeding,
g
p
p
g
j
y
p
,
g,
bruising, and/or infections at the site of cannula insertion. Rare complications due to blood 
g,
p
sampling are syncope, thrombophlebitis, and accidental punctures of an artery or nerve. 
Based on an acceptable tolerability profile and manageable AEs, as well as preliminary PK results 
p
y p
g
,
p
y
and efficacy signals, further dose assessment of CyPep-1 (20 mg Q2W) in combination with 
y
g
,
y
p
(
g Q
)
pembrolizumab 400 mg every 6 weeks (Q6W) will be explored in a DLT Phase 1b portion with 
p
g
y
(Q
)
p
p
confirmation of a recommended dose for Phase 2. These data will underpin further assessment of 
p
the safety, tolerability, and preliminary efficacy of CyPep-1 in combination pembrolizumab. 
The risks of pembrolizumab administration are detailed in the IB.23 Pembrolizumab has been 
p
documented to cause immune-related adverse reactions, for which a series of measures are 
recommended (see Section 5.5.3.3). 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are provided in Table 6. 
Table 6. 
Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
Phase 1b 
Confirm the recommended CyPep-1 dose (20 mg 
Q2W) when administered by IT injection in 
combination with pembrolizumab  
 
Incidence, frequency, and seriousness of TEAEs; 
 
Incidence of DLTs; and 
 
Changes from baseline in vital signs, body weight, 
12-lead ECG parameters, and laboratory 
assessments. 
Phase 2a 
Assess the anti-tumor activity of CyPep-1 administered 
by IT injection in combination with pembrolizumab 
ORR based on radiological assessment according to 
RECIST v1.1 
Secondary Objectives 
Secondary Endpoints 
Phase 1b 
Evaluate the PK of CyPep-1 in combination with 
pembrolizumab 
 
Plasma concentration-time profile of CyPep-1 and, 
if detectable, the following derived PK 
parameters:  
o 
AUC; 
o 
Cmax; 
o 
Tmax;  
o 
CL; 
o 
t½; and 
o 
VD. 
Phase 2a 
Expand evaluation of efficacy CyPep-1 + 
pembrolizumab  
 
ORR according to iRECIST; 
 
DCR according to iRECIST and RECIST v1.1;  
 
DoR according to iRECIST and RECIST v1.1; 
 
PFS according to iRECIST and RECIST v1.1; and 
 
OS for up to 26 months from Cycle 1 Visit 1. 
Evaluate the safety and tolerability of CyPep-1 in 
combination with pembrolizumab 
 
Incidence, frequency, and seriousness of TEAEs; 
and 
 
Changes from baseline in vital signs, body weight, 
12-lead ECG parameters, and laboratory 
assessments. 

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Table 6. 
Objectives and Endpoints (Continued) 
Exploratory Objectives 
Exploratory Endpoints 
Analyze changes in biomarkers and tumor kinetics 
associated with the mode of action of CyPep-1 and 
pembrolizumab by tumor biopsy from injected lesions 
 
Number and relative change of tumor infiltrating 
immune cells; 
 
Expression of selected immune cell biomarkers; 
 
Change from baseline in target tumor lesion size 
over time, overall, and by injected versus 
non-injected lesions; 
 
Maximum decrease from baseline in target tumor 
lesions, overall, and by injected versus 
non-injected lesions; and  
 
Changes in new lesions treated with CyPep-1. 
Expand evaluation of anti-tumor activity of CyPep-1 
and pembrolizumab 
ORR according to itRECIST 
AUC = area under the curve; CL = systemic clearance; Cmax = peak plasma concentration; DCR = Disease Control Rate; 
DLT = dose-limiting toxicity; DoR = Duration of Response; ECG = electrocardiogram; iRECIST = immune-Response 
Evaluation Criteria in Solid Tumors; IT = intra-tumoral; itRECIST = intratumoral-Response Evaluation Criteria in Solid 
Tumors; ORR = Objective Response Rate; OS = Overall Survival; PFS = Progression Free Survival; PK = pharmacokinetic(s); 
Q2W = every 2 weeks; Q6W = every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; t½ = elimination 
half-life; TEAE = treatment-emergent adverse event; Tmax = time to reach peak plasma concentration; v = version; VD = volume 
of distribution. 
 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is an open-label, multi-center, non-randomized Phase 1b/2a study. The Phase 1b portion of 
the study (ie, the first 6 patients enrolled) will confirm the recommended CyPep-1 dose of 20 mg 
Q2W in combination with pembrolizumab 400 mg Q6W (see Section 3.1.1). The patients from the 
Phase 1b portion will continue to the Phase 2a portion of the study (approximately 90 patients in 
total will be enrolled, with 30 patients per arm). The Phase 2a portion of the study will have 3 arms 
including patients with advanced or metastatic head and neck squamous cell carcinoma (HNSCC), 
melanoma, or triple-negative breast cancer (TNBC) and will assess the efficacy, safety, and 
pharmacodynamics of CyPep-1 (20 mg Q2W) when administered directly into measurable tumor 
lesions in combination with the anti-PD-1 antibody pembrolizumab (400 mg Q6W) (see 
Section 3.1.2).  
The following 3 study arms will be included in the study:  
 Arm A will include patients who meet the following criteria: 
o Have histologically confirmed diagnosis of HNSCC (including nasopharyngeal squamous 
cell carcinoma); 
o Have advanced or metastatic HNSCC incurable by standard of care therapies; and 
o Have recurrent or metastatic HNSCC that has progressed on or failed both platinum-based 
chemotherapy AND an ICI (given either sequentially or concurrently). 
Note: Patients who received platinum-based chemotherapy with concurrent radiation for 
locally advanced HNSCC and experienced disease progression within 6 months may also 
be considered as having disease progression on platinum-based chemotherapy. 
 Arm B will include patients who meet the following criteria: 
o Have histologically confirmed diagnosis of malignant melanoma; 
o Do not have uveal melanoma; 
o Have advanced or metastatic melanoma incurable by standard of care therapies; 
o Have received a combination of a BRAF inhibitor and a MEK inhibitor if diagnosed with 
a BRAF-mutated melanoma and if clinically indicated; and 
o Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
either as monotherapy or in combination with other checkpoint inhibitors or other 
therapies. 
 Arm C will include patients who meet the following criteria: 
o Have histologically confirmed diagnosis of TNBC as per American Society of Clinical 
Oncology/College of American Pathologists (ASCO/CAP) guidelines;24  
o Have advanced or metastatic TNBC incurable by standard of care therapies;  

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o Have received sacituzumab govitecan chemotherapeutic treatment if clinically indicated; 
and  
o Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
either as monotherapy or in combination with other therapies (if ICI eligible based on 
PD-L1 status) OR have received prior systemic therapy with either an anthracycline- or 
taxane-containing regimen (if ICI non-eligible based on PD-L1 status). 
The study enrollment will follow a 1-stage design as shown in Figure 2. 
Figure 2. One-Stage Study Design 
 
HNSCC = head and neck squamous cell carcinoma; N = number of patients planned for each arm; TNBC = triple-negative breast 
cancer.  
After signing the informed consent form (ICF), patients will be assessed for study eligibility. The 
Screening Visits will be completed within 28 days of the start of treatment. Screening will include 
the identification of measurable tumor lesions as per Response Evaluation Criteria in Solid Tumors 
(RECIST) version (v)1.1. Patients with lesions appropriate for IT injection with CyPep-1 (injected 
lesions) should be identified and will receive up to 4 mL of CyPep-1, after it is ensured that they 
meet the Inclusion Criteria (see Section 4.1) and none of the Exclusion Criteria (see Section 4.2) 
per the Investigator. 
When more than 1 measurable lesion is present at screening, up to a maximum of 5 lesions total 
(and a maximum of 2 lesions per organ) representative of all involved organs should be identified 
as target lesions. Both injected and non-injected lesions identified at screening per RECIST v1.1 
may be target lesions and will be recorded and measured at baseline and followed for response. If 
a patient only has 1 measurable lesion, then this lesion will be identified as an injected lesion and 
will be evaluated for efficacy as a target lesion. In these cases, IT therapy will not be considered a 
loco-regional therapy exclusionary for measurability, and single lesions may be designated as 
injectable target lesions per intratumoral-RECIST (itRECIST). 

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After each of the first 3 CyPep-1 injections, a telephone call will be conducted once daily for the 
first 2 days and once approximately 1 week post injection to assess patients¶ symptoms and 
temperatures. 
AEs will be recorded from the time of signing the ICF until 30 days after the last dose of study 
treatment. All AEs that are considered serious will be monitored and recorded until 90 days 
(30 days if patients initiate new anti-cancer therapy) after the last dose of study treatment. Other 
safety assessments will be conducted as described in the Schedule of Assessments (Appendix A). 
The Data Monitoring Committee (DMC) will review accumulating safety data in regular intervals 
as per the DMC charter. 
An overview of the study flow is presented in Figure 3. 
Figure 3. Study Flow 
 
The Phase 1b portion of the study will comprise of the first 6 patients enrolled in the study. After the first 6 patients have completed 
the DLT period (Cycle 1 [initial 6 weeks of study treatment]), the DMC and Sponsor will review safety and tolerability data prior 
to the enrollment of the remainder of the patients into the Phase 2a portion of the study. 
DLT = dose-limiting toxicity; DMC = Data Monitoring Committee; EoT = End of Treatment; FU = follow-up; 
IT = intra-tumoral(ly); IV = intravenous(ly); n = number of treatment cycle; Q6W = every 6 weeks; Q8W = every 8 weeks; 
Screen = screening.  
3.1.1 
Phase 1b 
The Phase 1b portion of the study will comprise of the first 6 patients enrolled in the study to 
confirm the recommended CyPep-1 dose (20 mg Q2W) based on safety and tolerability 
observations.  
Patients will receive IT injections of a fixed concentration of CyPep-1 Q2W beginning at Cycle 1 
Visit 1. Pembrolizumab will be administered IV at a fixed dose Q6W beginning at Cycle 1 Visit 1. 
Patients must be observed for 4 hours post injection for PK monitoring on Cycle 1 Day 15. The 
plasma concentration-time profile of CyPep-1 and, if detectable, the derived PK parameters will 
be assessed. 
The DLT period for the Phase 1b portion of the study will be Cycle 1 (initial 6 weeks of study 
treatment); see Section 3.1.1.1. After the first 6 patients have completed the DLT period, the DMC 
and Sponsor will review safety and tolerability data prior to the enrollment of the patients into the 
Phase 2a portion of the study. If 
2 DLTs are observed in the first 6 patients, then the 
recommended CyPep-1 dose will be confirmed and enrollment of the remainder of the patients 
should continue. 

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If >2 of the 6 patients develop a DLT at the recommended CyPep-1 dose level (5 mg/mL dose 
concentration), then the MTD of CyPep-1 will be assumed to have been exceeded and dose 
de-escalation will be conducted to determine the MTD. At least 6 patients will be treated at 
CyPep-1 dose level -1 (2 mg/mL dose concentration). If necessary, due to >2 DLTs in the dose 
level -1 cohort, a further reduction to dose level -2 (0.5 mg/mL dose concentration) will be 
performed. 
Dose de-escalation will proceed according to the following rules: 
 If 2 out of 6 patients develop a DLT, the MTD will be declared; or 
 If >2 out of 6 patients develop a DLT, the dose will be de-escalated to the next lower dose. 
The MTD will guide confirmation, by agreement of the DMC and the Sponsor, of a recommended 
Phase 2 dose (RP2D). The RP2D may be equivalent to the MTD or may be a dose below the MTD 
and will be dependent on an acceptable tolerability profile and manageable AEs. 
The patients from Phase 1b will continue to the Phase 2a portion of the study. After the DMC 
reviews the safety data, feedback will be provided to the Sponsor regarding the further conduct of 
the study, see Section 3.1.2. 
3.1.1.1 
Dose-limiting toxicities 
All toxicities will be graded using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0 based on the Investigator assessment. 
The DLT window of observation will be during Cycle 1 (initial 6 weeks of study treatment). 
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the Investigator to be possibly, probably, or definitely related to study treatment 
administration:  
1. Grade 4 non-hematologic toxicity (not laboratory); 
2. Grade 4 hematologic toxicity lasting 7 days, except thrombocytopenia: 
o Grade 4 thrombocytopenia of any duration; or 
o Grade 3 thrombocytopenia associated with clinically significant bleeding. 
3. Any non-hematologic AE Grade 3 in severity should be considered a DLT, with the following 
exceptions:  
o Grade 3 fatigue lasting 3 days;  
o Grade 3 diarrhea, nausea, or vomiting unless it persists for >3 days despite the use of 
anti-emetics or anti-diarrheals per standard of care; or 
o Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of 
care. 
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
o Clinically significant medical intervention is required to treat the patient; 
o The abnormality leads to hospitalization; 
o The abnormality persists for >1 week; or 

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o The abnormality results in a drug-induced liver injury.  
o Exceptions: Clinically non-significant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc. Isolated laboratory abnormalities Grade 3 
(not present at baseline) that resolve to <Grade 1 in <3 days without clinical sequelae or 
need for therapeutic intervention. 
5. Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) for more 
than 1 hour; or 
o Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) or a 
sustained temperature of 38°C (100.4°F) for more than 1 hour with life-threatening 
consequences and urgent intervention indicated. 
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; 
7. Delay in administration of CyPep-1 for >7 days; 
8. Any single instance of aspartate aminotransferase and/or alanine aminotransferase >3 × upper 
limit of normal (ULN) AND concurrent total bilirubin >2 × ULN that is not thought to be due 
to disease progression or other medical illness (ie, liver function abnormalities that meet the 
criteria of Hy¶s Law); 
9. Any treatment-related toxicity that causes the patient to discontinue treatment during Cycle 1; 
10. Missing >25% of study treatment doses as a result of drug-related AE(s) during the first cycle; 
or 
11. Grade 5 toxicity. 
3.1.2 
Phase 2a 
The Phase 2a portion of the study will comprise of all approximately 90 patients (including the 
first 6 patients assessed in the Phase 1b portion) to assess the efficacy, safety, and 
pharmacodynamics of CyPep-1 (20 mg Q2W) in combination with the anti-PD-1 antibody 
pembrolizumab (400 mg Q6W). Patients will receive IT injections of a fixed concentration of 
CyPep-1 Q2W beginning at Cycle 1 Visit 1. Pembrolizumab will be administered IV at a fixed 
dose Q6W beginning at Cycle 1 Visit 1. Each treatment cycle will be 6 weeks, and treatment will 
continue for a maximum of 18 cycles (108 weeks) or until the occurrence of confirmed progressive 
disease (PD), excessive toxicity, death, or withdrawal of consent. Patients who complete all 
18 cycles, which is the Food and Drug Administration (FDA)-approved maximum duration of 
pembrolizumab use, may continue receiving CyPep-1 at the current dose if determined beneficial 
by the Investigator and following approval of the Sponsor. CyPep-1 monotherapy may proceed 
until the occurrence of confirmed PD, excessive toxicity, death, or withdrawal of consent. 
Radiological assessments and local measurements of tumor lesion(s), according to RECIST v1.1, 
will be conducted and evaluated at baseline (screening) and at 8-week intervals after the first dose 
of CyPep-1 through the last Progression Follow-up Visit during the Follow-up Period (up to 
approximately 26 months after the start of treatment). Radiological assessments can be more 
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are the preferred scanning procedures to be used in this study. Selection of either MRI or CT should 
be based on individual patient considerations and local regulations and is at the Investigator¶s 
discretion. Once selected for each patient, the same scanning procedure should be used consistently 
at all remaining visits. Scans will be collected and held centrally for potential central radiologic 
review. When radiological PD is identified by the Investigator, PD is to be confirmed by another 
set of scans performed approximately 4 weeks to 8 weeks later according to immune-RECIST 
(iRECIST) guidelines (Appendix D). If PD is not confirmed, study treatment will continue until 
progression is confirmed.  
Patients who have confirmed PD or discontinue treatment for any other reason will be followed-up 
by phone call every 3 months for survival until the end of study (approximately 26 months after 
the start of treatment).  
Unless death or withdrawal of consent occurs, patients who received any injection of CyPep-1 will 
have a Safety Follow-up Visit 30 days after the last CyPep-1 injection. If the End of Treatment 
(EoT) Visit occurs more than 30 days after the last dose of study treatment, the Safety Follow-up 
Visit will be skipped. Patients who terminate treatment prior to 18 cycles will continue to be 
followed for progression every 8 weeks (Q8W) from start of study treatment until the occurrence 
of confirmed PD as defined by iRECIST (Appendix D) or start of new anti-cancer treatment. These 
patients will also be followed for survival for up to approximately 26 months after the start of 
treatment.  
3.1.3 
Data Monitoring Committee 
The monitoring of the safety and tolerability of CyPep-1 + pembrolizumab will be performed by 
the DMC. 
This will include all the patients in the Phase 1b portion and thereafter, all patients who have 
entered the study. This will be conducted on a regular basis, as defined in the DMC charter.  
After the DMC reviews the safety data, feedback will be provided to the Sponsor regarding the 
further conduct of the study. The DMC will be comprised of independent members or designees. 
The DMC will strive for a consensus opinion regarding the data reviewed.  
At the end of each DMC review meeting, the DMC will provide 1 of the following feedback to the 
Sponsor: 
 The study is proceeding in line with the study protocol; or 
 The study is not proceeding in line with the study protocol and/or there is a possible change in 
the benefit/risk ratio.  
The observation of any Discontinuation of Enrollment Criteria (Section 4.5.3) for Phase 2a patients 
must trigger the immediate decision by the Sponsor to stop recruitment and organize an urgent 
DMC meeting, which will assess the causality of the observed AEs and the fulfillment of the 
criteria. The DMC will formulate a recommendation to resume recruitment, discontinue the 
involved cohort, or stop the study. 
The Sponsor will act upon the feedback as appropriate, ie, the final decision will be made by the 
Sponsor. The Sponsor or designee will notify the study team (ie, the responsible project manager) 
of the final decision regarding the DMC feedback, including any actions to be taken. The Sponsor 
or designee will communicate the DMC feedback and/or final decision of the Sponsor to all 

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Investigators and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), if 
applicable. 
3.1.4 
Coronavirus Disease 2019 Contingency Measures 
In cases of COVID-19 limitations, it is the Investigator¶s responsibility to assure the safety of 
patients via phone or video contact to assess the patient¶s well-being and assess for any AEs and 
collect additional clinical data as best as possible. Where available and appropriate, home health 
care may be considered to facilitate monitoring of safety and study continuity. Documentation of 
these cases and the study site¶s management of patients should be recorded in the Investigator 
study files. The impacts of the COVID-19 pandemic on the outcomes of this study, including any 
protocol deviations that result from COVID-19 illness and/or COVID-19 control measures, will 
be discussed in the CSR. In the absence of a COVID-19 impact, it is expected that Investigators 
and patients follow the protocol requirements as set forth. 
3.2 
Study Indications 
The indications of this study are advanced or metastatic HNSCC, melanoma, or TNBC. 

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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
No waivers for inclusion or exclusion criteria will be given. 
4.1.1 
General Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Are 18 years of age or older on the day of signing informed consent; 
2. Provide written informed consent and are able to comply with study procedures and 
assessments; 
3. Have measurable disease per RECIST v1.1 as assessed by the local site Investigator/radiology. 
Lesions situated in a previously irradiated area are considered measurable if progression has 
been demonstrated in such lesions; 
4. Have at least 1 non-ulcerated, measurable, and accessible lesion for IT injection with a 
maximum diameter of 5 cm; 
5. Are able to provide tissue from a core or excisional biopsy at screening or have an acceptable 
stored tumor sample available that was collected within 90 days prior to screening;  
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix C); 
7. Have a life expectancy 3 months, as determined by the Investigator; 
8. Female patients of non-childbearing potential must be either surgically sterile (hysterectomy, 
bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before 
screening), post-menopausal, defined as spontaneous amenorrhea for at least 2 years, or with 
follicle-stimulating hormone in the post-menopausal range at screening; 
9. Female patients of childbearing potential (defined as <2 years after last menstruation or not 
surgically sterile) must have a negative serum pregnancy test at screening and agree to use a 
highly effective method for contraception from the time of signing the ICF until at least 
120 days after the last administration of study treatment. Highly effective methods of 
contraception are birth control methods with a failure rate of <1% per year when used 
consistently and correctly, including the following: 
o Combined estrogen- and progestin-containing hormonal contraception associated with 
inhibition of ovulation given orally, intravaginally, or transdermally; progestin-only 
hormonal contraception associated with inhibition of ovulation given orally, by injection, 
or by implant; intrauterine devices; and intrauterine hormone-releasing systems; 
o Female sterilization (surgical bilateral oophorectomy with/without hysterectomy, total 
hysterectomy, bilateral tubal occlusion/ligation) at least 26 weeks prior to first study 
treatment; 
o Sterilization of male partner (at least 6 months prior to first study treatment dose); and 
o Complete sexual abstinence. Periodic abstinence (eg, calendar) and withdrawal are not 
acceptable. Sexual abstinence is considered a highly effective method only if defined as 

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refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the patient. 
10. Male patients able to father children must agree to use 2 acceptable methods of contraception 
throughout the study (eg, condom plus spermicidal gel). Sperm donation is not recommended 
from the time of signing the ICF until at least 120 days after the last administration of study 
treatment; and 
11. Have adequate organ function as defined in Table 7. Specimens must be collected within 
72 hours prior to the start of study treatment at Cycle 1 Visit 1. 
Table 7. 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
ANC 
1500/µL 
Platelets 
100,000/µL 
Hemoglobin1 
9.0 g/dL or 5.6 mmol/L 
Renal 
Creatinine OR 
Measured or calculated CrCl2 (GFR can also be used 
in place of creatinine or CrCl) 
1.5 × ULN OR 
30 mL/min for patients with creatinine levels 
>1.5 × institutional ULN 
Hepatic 
Total bilirubin 
1.5 × ULN OR direct bilirubin ULN for 
patients with total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
2.5 × ULN ( 5 × ULN for patients with liver 
metastases) 
This table includes eligibility-defining laboratory value requirements for treatment. 
1. 
Criteria must be met without pRBC transfusion within the prior 2 weeks. Patients can be on a stable dose of 
erythropoietin (approximately 3 months). 
2. 
CrCl should be calculated per institutional standard. 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); ANC = absolute neutrophil count; AST 
(SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; 
GFR = glomerular filtration rate; pRBC = packed red blood cell; ULN = upper limit of normal. 
4.1.2 
Inclusion Criteria for Arm A 
Patients who meet all of the general Inclusion Criteria (Section 4.1.1) and the following additional 
criteria will be eligible for inclusion in Arm A: 
1. Have histologically confirmed diagnosis of HNSCC (including nasopharyngeal squamous cell 
carcinoma); 
2. Have advanced or metastatic HNSCC incurable by standard of care therapies; and  
3. Have recurrent or metastatic HNSCC that has progressed on or failed both platinum-based 
chemotherapy AND an ICI (given either sequentially or concurrently). 
Note: Patients who received platinum-based chemotherapy with concurrent radiation for 
locally advanced HNSCC and experienced disease progression within 6 months may also be 
considered as having disease progression on platinum-based chemotherapy. 

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4.1.3 
Inclusion Criteria for Arm B 
Patients who meet all of the general Inclusion Criteria (Section 4.1.1) and the following additional 
criteria will be eligible for inclusion in Arm B: 
1. Have histologically confirmed diagnosis of malignant melanoma;  
2. Do not have uveal melanoma; 
3. Have advanced or metastatic melanoma incurable by standard of care therapies;  
4. Have received a combination of a BRAF inhibitor and a MEK inhibitor if diagnosed with a 
BRAF-mutated melanoma and if clinically indicated; and  
5. Have failed or progressed on or after treatment with a checkpoint inhibitor administered either 
as monotherapy or in combination with other checkpoint inhibitors or other therapies. 
4.1.4 
Inclusion Criteria for Arm C 
Patients who meet all of the general Inclusion Criteria (Section 4.1.1) and the following additional 
criteria will be eligible for inclusion in Arm C: 
1. Have histologically confirmed diagnosis of TNBC as per ASCO/CAP guidelines;24  
2. Have advanced or metastatic TNBC incurable by standard of care therapies;  
3. Have received sacituzumab govitecan chemotherapeutic treatment if clinically indicated; and  
4. Have failed or progressed on or after treatment with a checkpoint inhibitor administered either 
as monotherapy or in combination with other therapies (if ICI eligible based on PD-L1 status) 
OR have received prior systemic therapy with either an anthracycline- or taxane-containing 
regimen (if ICI non-eligible based on PD-L1 status). 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Have only non-palpable cutaneous infiltrations (eg, breast cancer cutaneous carcinomatosis); 
2. Have had anti-cancer therapy within 4 weeks prior to the first dose of study treatment (2 weeks 
for palliative radiotherapy); 
Note: Patients must have recovered from all AEs due to previous therapies to Grade 1 or 
baseline (alopecia is an allowable exception). Upon discussion with the Sponsor, patients with 
Grade 2 neuropathy or endocrine-related AEs requiring treatment or hormone replacement 
may be eligible. 
Note: If the patient had major surgery, the patient must have recovered adequately from the 
procedure and/or any complications from the surgery prior to starting study intervention.  
3. Have participated in a clinical trial and received an investigational therapy within 30 days prior 
to the first dose of study treatment;  

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4. Have received or will receive a live or live attenuated vaccine within 30 days prior to the first 
dose of study treatment;  
Note: Seasonal flu vaccines that do not contain live vaccine are permitted. COVID-19 vaccines 
are only permitted with documentation of the date of the vaccine if the last dose of vaccine was 
administered >14 days prior to the first dose of study treatment. The COVID-19 booster 
vaccine must be administered at least 14 days prior to the first dose of study treatment and is 
not allowed during the first 3 months of the Treatment Period. 
5. Have tested positive for SARS-CoV-2 infection within 14 days prior to the Screening Visit; 
Note: Patients who have had a known SARS-CoV-2 infection >14 days prior to the Screening 
Visit are permitted at Investigator discretion and must present with no symptoms. 
6. Have had a major surgical procedure within 14 days prior to the first dose of study treatment; 
7. Are expected to require a systemic or localized anti-neoplastic therapy during participation in 
this study, excluding localized palliative radiotherapy to tumors not selected for evaluation of 
treatment response; 
Note: Use of denosumab for patients with bone metastasis is allowed. 
8. Are pregnant or breastfeeding; 
9. Have clinical evidence of a secondary malignancy actively progressing or requiring active 
treatment other than curative therapies for early stage (carcinoma in situ or Stage 1) carcinomas 
or non-melanoma skin cancer; 
10. Have had any autoimmune disease requiring immunosuppressive therapy (ie, use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs) within 2 years prior to the 
first dose of study treatment;  
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is allowed.  
11. Have a condition requiring continuous systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive agents within 2 weeks prior to the 
first dose of study treatment. Inhaled, intranasal, or topical (only on areas outside the injected 
lesion[s]) and physiological replacement doses of up to 10 mg daily prednisone equivalent are 
permitted in the absence of active autoimmune disease; 
12. Have abnormal or clinically significant coagulation parameters as determined by the 
Investigator (eg, prothrombin time [PT], international normalized ratio [INR], activated partial 
thromboplastin time [aPTT]) unless patients are on anti-coagulants in which case it must be 
within appropriate clinical levels; 
Note: Patients who are on anti-coagulants must be able to switch to a low molecular weight 
heparin or equivalent prior to Cycle 1 Day 1 and continue during the Treatment Period. 
13. Have a significant history or clinical manifestation of any allergic disorders and/or Quincke¶s 
edema (as determined by the Investigator) capable of significantly altering the absorption of 
drugs, of constituting a risk when taking CyPep-1 or pembrolizumab, or of interfering with the 
interpretation of the data; 

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14. Have a known hypersensitivity to any component of CyPep-1 or pembrolizumab; 
15. Have a history of adverse reactions from treatment with ICIs, including pembrolizumab, which 
resulted in discontinuation of ICI or pembrolizumab or has ongoing pembrolizumab-related 
toxicity event(s) as per treatment-limiting toxicity definitions, except patients with ongoing 
endocrine disorders that are managed with replacement therapy (ie, hypothyroidism related to 
prior pembrolizumab treatment); 
16. Have an active infection requiring systemic therapy; 
17. Have a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known 
active Hepatitis C virus (defined as Hepatitis C virus RNA [qualitative] is detected) infection; 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health 
authority. 
18. Have had radiotherapy within 2 weeks prior to the first dose of study treatment, are in recovery 
from radiation toxicity, or have had radiation pneumonitis; 
19. Have a history of non-infectious pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease; 
20. Have had a prior allogeneic tissue/solid organ transplant, stem cell, or bone marrow transplant; 
21. Have active human immunodeficiency virus (HIV). Patients are eligible when on stable 
anti-retroviral therapy (no change in medication or dose) for at least 4 weeks prior to screening, 
have confirmed virologic suppression with HIV RNA less than 50 copies/mL or the lower limit 
of quantification (below the limit of detection) using the locally available assay at the time of 
screening and for at least 12 weeks prior to screening, and have a CD4+ T cell count 
>350 cells/mm3 at screening. HIV-infected patients with a history of Kaposi sarcoma and/or 
Multicentric Castleman Disease will be excluded; 
22. Have 4 or more sites involved, including the primary cancer; 
Note: A site is defined as an organ (eg, lung, liver, or brain) or a system (eg, lymphatic or 
central nervous system [CNS]). 
23. Have a CNS metastasis that is symptomatic, progressing, or that requires current therapy (eg, 
evidence of new or enlarging CNS metastasis, carcinomatous meningitis, or new neurological 
symptoms attributable to CNS metastasis);  
24. Have a QTcF >480 ms at screening, history of long or short QT syndrome, Brugada syndrome, 
QTc prolongation, or Torsade de Pointes, with the exception of patients with controlled atrial 
fibrillation, pacemaker, or bundle branch block as the QTc will be prolonged due to the 
widened QRS; 
25. Are an adult under legal protection, are vulnerable, or lack the capacity to give informed 
consent, such as: 
o Persons deprived of liberty by a judicial or administrative decision; 
o Adult persons subject to a legal protection measure (under supervision/under 
guardianship); or  
o Persons under a judicial protection measure; or 

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26. Have a history of 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 make participation in the study not in the best interest of the patient, 
in the opinion of the Investigator. 
4.3 
Retesting 
If laboratory abnormalities during screening are considered by the Investigator to be transient, then 
the laboratory tests may be repeated once during screening. The Investigator¶s rationale for 
retesting should be documented. If the retest result is no longer exclusionary, the patient may be 
enrolled in the study. 
4.4 
Rescreening 
A patient who is screened and does not meet the study eligibility criteria may be considered for 
rescreening upon Sponsor and/or Medical Monitor consultation and approval. Rescreened patients 
will keep the original patient identification. Rescreening should occur no less than 5 days after the 
last Screening Visit. 
4.5 
Withdrawal Criteria 
A distinction must be made between patients who discontinue study treatment prematurely and 
patients who are discontinued from the study.  
In all cases of impending premature study treatment discontinuation or patient requests for 
withdrawal from study visits, the Investigators should discuss with the patient his/her options for 
continuing in the study. The Investigator should ensure he/she understands the reasons for a 
patient¶s desire to discontinue study treatment or withdraw from the study prior to completion and 
document these reasons in the electronic case report form (eCRF). 
4.5.1 
Discontinuation of Study Treatment 
A patient may be discontinued from study treatment before the end of the Treatment Period but 
remain in the study for safety follow-up for any of the following reasons: 
 A confirmed complete response (CR) is attained, and the patient has been treated for at least 
8 cycles (ie, at least 24 weeks), including 2 cycles of the combination treatment (including 
2 doses of pembrolizumab) from the date when the initial CR was declared; 
 Occurrence of a severe systemic hypersensitivity reaction that is uncontrolled with standard 
management or requires high dose steroids; 
 Occurrence of necrosis, ulcerations, bleeding, or any other serious complication in healthy 
tissues surrounding the injected tumor; 
 Occurrence of injected tumor ulcerations that do not show a healing trend in a 3-week period; 
 Occurrence of any other 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, 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; 

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 Pregnancy; 
 Requirement of prohibited concomitant medication; 
 Patient requests discontinuation of study treatment for any reason; and/or 
 Patient failure to comply with protocol requirements or study-related procedures.  
If a patient discontinues CyPep-1 but remains eligible to participate in the study after review by 
the Investigator and Medical Monitor, pembrolizumab treatment will be continued Q6W as per 
institutional guidelines until PD, unacceptable toxicity, or consent withdrawal by patient for a 
maximum of 18 treatment cycles. All assessments will continue to be performed according to the 
Schedule of Assessments (Appendix A). 
If a patient discontinues pembrolizumab but remains eligible to participate in the study after review 
by the Investigator and Medical Monitor, CyPep-1 treatment will be continued Q2W until PD, 
unacceptable toxicity, or consent withdrawal by patient for a maximum of 18 treatment cycles. All 
assessments will continue to be performed according to the Schedule of Assessments 
(Appendix A). 
4.5.2 
Discontinuation From the Study 
Participation of a patient in this study may be discontinued for any of the following reasons: 
 Patient requests discontinuation or withdraws consent to participate in the study for any reason;  
 Discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in the study; 
 Demonstration of efficacy that would warrant study stopping; 
 Study data are not sufficiently complete and/or evaluable;  
 Determination of futility;  
 The Sponsor decides to suspend or discontinue testing, evaluation, or development of the study 
treatment; and/or 
 The regulatory authority decides to terminate the study. 
4.5.3 
Discontinuation of Enrollment Criteria 
Discontinuation of enrollment will occur for Phase 2a patients who meet any of the following 
criteria: 
 Any CTCAE Grade 5 toxicity attributed to CyPep-1; 
 SUSAR Grade 4 CTCAE attributed to any component of the treatment combination; 
 Signal of increased frequency or severity of any irAEs leading to permanent discontinuation 
as defined in Table 10; 
 Site of injection AEs Grade 4 CTCAE caused by CyPep-1 that do not revert to Grade 1 in a 
2 week period; or 
 Any CyPep-1 related toxicity resulting in liver abnormality meeting Hy¶s Law criteria. 

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The observation of any of these criteria must trigger the immediate decision by the Sponsor to stop 
recruitment and organize an urgent DMC meeting, which will assess the causality of the observed 
AEs and the fulfillment of the discontinuation of enrollment criteria (above). The DMC will 
formulate a recommendation to resume recruitment, discontinue the involved cohort, or stop the 
study. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
EoT Visit (7 [±2] days after the last CyPep-1 or pembrolizumab administration). Withdrawal from 
the study will not affect or prejudice the patient¶s further care or treatment. 
In the case of a patient lost to follow-up, attempts to contact the patient must be made and 
documented in the patient¶s medical records. 
Patients who are discontinued from the study before receiving at least 1 dose of study treatment 
will be replaced. Patients who are discontinued from the study after receiving at least 1 dose of 
CyPep-1 or pembrolizumab will not be replaced. In case of pembrolizumab-related toxicity 
( Grade 2 according to the NCI CTCAE v5.0), treatment with CyPep-1 will be delayed and 
planned after a review by the Investigator and Medical Monitor. If CyPep-1 treatment is delayed 
>7 days, that dose will be omitted. After 14 days of delay, consult with the Sponsor. See 
Section 5.5.3.3 for management of dose toxicity.  

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5
STUDY TREATMENTS 
5.1
Treatment Groups 
The following 3 study arms will be included in the study:  
Arm A will include patients who meet the following criteria: 
o
Have histologically confirmed diagnosis of HNSCC (including nasopharyngeal squamous 
cell carcinoma); 
o
Have advanced or metastatic HNSCC incurable by standard of care therapies; and 
o
Have recurrent or metastatic HNSCC that has progressed on or failed both platinum-based 
chemotherapy AND an ICI (given either sequentially or concurrently). 
Note: Patients who received platinum-based chemotherapy with concurrent radiation for 
locally advanced HNSCC and experienced disease progression within 6 months may also 
be considered as having disease progression on platinum-based chemotherapy. 
Arm B will include patients who meet the following criteria: 
o
Have histologically confirmed diagnosis of malignant melanoma; 
o
Do not have uveal melanoma; 
o
Have advanced or metastatic melanoma incurable by standard of care therapies; 
o
Have received a combination of a BRAF inhibitor and a MEK inhibitor if diagnosed with 
a BRAF-mutated melanoma and if clinically indicated; and 
o
Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
either as monotherapy or in combination with other checkpoint inhibitors or other 
therapies. 
Arm C will include patients who meet the following criteria: 
o
Have histologically confirmed diagnosis of TNBC as per ASCO/CAP guidelines;24  
o
Have advanced or metastatic TNBC incurable by standard of care therapies; 
o
Have received sacituzumab govitecan chemotherapeutic treatment if clinically indicated; 
and  
o
Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
either as monotherapy or in combination with other therapies (if ICI eligible based on 
PD-L1 status) OR have received prior systemic therapy with either an anthracycline- or 
taxane-containing regimen (if ICI non-eligible based on PD-L1 status). 
5.2
Rationale for Dosing 
5.2.1
CyPep-1 
The cumulative maximal dose of CyPep-1 is 20 mg (4 mL of 5 mg/mL) per treatment day. The 
selected dose is based on safety and tolerability data from the Phase 1 dose escalation part of the 
CICILIA study that used the rule-based ³3+3´ dose escalation design. Dose escalation proceeded 
according to escalation rules that were based on the number of DLTs observed per dose level. As 
5
STUDY TREATMENTS 
5.1
Treatment Groups 
The following 3 study arms will be included in the study: 
Arm A will include patients who meet the following criteria: 
Have histologically confirmed diagnosis of HNSCC (including nasopharyngeal squamous 
f
o
g
cell carcinoma); 
Have advanced or metastatic HNSCC incurable by standard of care therapies; and 
o
Have recurrent or metastatic HNSCC that has progressed on or failed both platinum-based 
o
p
g
chemotherapy AND an ICI (given either sequentially or concurrently). 
Note: Patients who received platinum-based chemotherapy with concurrent radiation for
p
py
locally advanced HNSCC and experienced disease progression within 6 months may also
n
y
p
p
g
be considered as having disease progression on platinum-based chemotherapy. 
Arm B will include patients who meet the following criteria:
Have histologically confirmed diagnosis of malignant melanoma; 
o
Do not have uveal melanoma; 
o
Have advanced or metastatic melanoma incurable by standard of care therapies; 
o
Have received a combination of a BRAF inhibitor and a MEK inhibitor if diagnosed with
o
a BRAF-mutated melanoma and if clinically indicated; and 
Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
o
p
g
p
either as monotherapy or in combination with other checkpoint inhibitors or other 
therapies. 
Arm C will include patients who meet the following criteria:
Have histologically confirmed diagnosis of TNBC as per ASCO/CAP guidelines;
f
24
o
Have advanced or metastatic TNBC incurable by standard of care therapies; 
o
Have received sacituzumab govitecan chemotherapeutic treatment if clinically indicated; 
o
and 
Have failed or progressed on or after treatment with a checkpoint inhibitor administered 
o
p
g
p
either as monotherapy or in combination with other therapies (if ICI eligible based on 
py
p
(
g
PD-L1 status) OR have received prior systemic therapy with either an anthracycline- or
)
p
y
py
taxane-containing regimen (if ICI non-eligible based on PD-L1 status). 
5.2
CyPep-1 
The cumulative maximal dose of CyPep-1 is 20 mg (4 mL of 5 mg/mL) per treatment day. The 
y
p
g (
g
) p
y
selected dose is based on safety and tolerability data from the Phase 1 dose escalation part of the 
y
y
p
CICILIA study that used the rule-based ³3+3´ dose escalation design. Dose escalation proceeded 
according to escalation rules that were based on the number of DLTs observed per dose level. As
y
g
p

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there were no DLTs observed during the Phase 1 part of the CICILIA study, the highest 
administered CyPep-1 dose was selected as a safe dose to take forward into this Phase 1b/2a study; 
see Section 1.1.2. If the recommended dose concentration of 5 mg/mL is not confirmed in this 
Phase 1b study, dose de-escalation will be conducted to determine the MTD; see Section 3.1.1. 
The CyPep-1 dose concentration of the recommended dose level and 2 de-escalation dose levels 
are listed in Table 8. 
Table 8. 
Dose Cohorts 
Dose Cohort 
CyPep-1 Dose 
Concentration 
Cumulative Maximum Dose 
(Assumes 4 mL per Treatment Day) 
Dose Level 0 (recommended dose) 
5 mg/mL 
20 mg
Dose Level -1 
2 mg/mL 
8 mg
Dose Level -2 
0.5 mg/mL 
2 mg
5.2.2
Pembrolizumab 
The planned dose of pembrolizumab for this study is 400 mg administered IV Q6W, and it has 
been approved in many countries.25,26 A 400 mg Q6W dosing regimen is expected to have a similar 
benefit-risk profile as 200 mg every 3 weeks (Q3W) in all treatment settings in which 200 mg 
Q3W pembrolizumab is currently appropriate.27 Specifically, the dosing regimen of 400 mg Q6W
for pembrolizumab is considered adequate based on modeling and simulation analyses, given the 
pharmacokinetic simulations demonstrating the following in terms of pembrolizumab exposures: 
Average concentration over the dosing interval (or area under the curve) at 400 mg Q6W is 
similar to that at the approved 200 mg Q3W dose, thus bridging efficacy between dosing 
regimens; 
Trough concentrations at 400 mg Q6W are generally within the range of those achieved with 
2 mg/kg or 200 mg Q3W in the majority (>99%) of patients; 
Cmax at 400 mg Q6W are well below the Cmax for the highest clinically tested dose of 10 mg/kg 
Q2W, supporting that the safety profile for 400 mg Q6W should be comparable to the 
established safety profile of pembrolizumab; and 
Exposure-response for pembrolizumab has been demonstrated to be flat across indications, and 
OS predictions in melanoma and non-small cell lung cancer demonstrate that efficacy at 
400 mg Q6W is expected to be similar to that at 200 mg or 2 mg/kg Q3W, given the similar 
exposures; thus 400 mg Q6W is expected to be efficacious across indications. 
The rationale for using the recommended dose of CyPep 1 in combination with pembrolizumab is 
supported by the safety profile of the monotherapy phase of the CICILA study. Further evaluation 
of safety, tolerability, and efficacy will be performed as part of this Phase 1b/2a study and 
recommendations can be made by the DMC. 
5.3
Randomization and Blinding 
This is an open-label, non-randomized study. No blinding is necessary.  
5.4
Breaking the Blind 
Procedures for breaking the blind are not applicable for this study.  
there were no DLTs observed during the Phase 1 part of the CICILIA study, the highest 
g
p
y,
g
administered CyPep-1 dose was selected as a safe dose to take forward into this Phase 1b/2a study;
y
p
y;
see Section 1.1.2. If the recommended dose concentration of 5 mg/mL is not confirmed in this 
g
Phase 1b study, dose de-escalation will be conducted to determine the MTD; see Section 3.1.1. 
y,
;
The CyPep-1 dose concentration of the recommended dose level and 2 de-escalation dose levels
y
p
are listed in Table 8. 
Table 8. 
Dose Cohorts 
CyPep-1 Dose 
Cumulative Maximum Dose 
Dose Cohort 
y
p
Concentration 
(Assumes 4 mL per Treatment Day)
Dose Level 0 (recommended dose) 
5 mg/mL 
p
20 mg
(
Dose Level -1 
g
2 mg/mL 
g
8 mg
Dose Level -2 
g
0.5 mg/mL 
g
2 mg
5.2.2
Pembrolizumab 
The planned dose of pembrolizumab for this study is 400 mg administered IV Q6W, and it has
p
p
been approved in many countries.25,26
y
g
Q
,
A 400 mg Q6W dosing regimen is expected to have a similar 
pp
y
g Q
g
g
p
benefit-risk profile as 200 mg every 3 weeks (Q3W) in all treatment settings in which 200 mg 
p
g
y
Q3W pembrolizumab is currently appropriate.
(
27Q
)
g
g
Specifically, the dosing regimen of 400 mg Q6W
Q
p
y pp
p
p
y,
g
g
g Q
for pembrolizumab is considered adequate based on modeling and simulation analyses, given the
p
q
g
y
, g
pharmacokinetic simulations demonstrating the following in terms of pembrolizumab exposures:
Average concentration over the dosing interval (or area under the curve) at 400 mg Q6W is
g
g
(
)
g Q
similar to that at the approved 200 mg Q3W dose, thus bridging efficacy between dosing
regimens; 
Trough concentrations at 400 mg Q6W are generally within the range of those achieved with 
g
g Q
g
y
2 mg/kg or 200 mg Q3W in the majority (>99%) of patients; 
Cmax at 400 mg Q6W are well below the Cmax for the highest clinically tested dose of 10 mg/kg
g Q
g
y
g g
Q2W, supporting that the safety profile for 400 mg Q6W should be comparable to the 
Q
,
pp
g
y p
established safety profile of pembrolizumab; and 
Exposure-response for pembrolizumab has been demonstrated to be flat across indications, and
p
p
p
,
OS predictions in melanoma and non-small cell lung cancer demonstrate that efficacy at
p
g
y
400 mg Q6W is expected to be similar to that at 200 mg or 2 mg/kg Q3W, given the similar 
g Q
p
g
g g Q
, g
exposures; thus 400 mg Q6W is expected to be efficacious across indications. 
The rationale for using the recommended dose of CyPep 1 in combination with pembrolizumab is 
g
y
p
p
supported by the safety profile of the monotherapy phase of the CICILA study. Further evaluation 
t
pp
y
y p
py p
y
of safety, tolerability, and efficacy will be performed as part of this Phase 1b/2a study and
t
y,
y,
y
recommendations can be made by the DMC.

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5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The IT formulation of CyPep-1 is a clear and colorless aqueous solution (5 mg/mL) for 
subcutaneous administration supplied in single-use vials. The CyPep-1 (5 mg/mL) solution 
consists of the drug substance CyPep-1 dissolved in 0.9% sodium chloride solution. Each vial 
contains a deliverable volume of 2 mL of CyPep-1 solution that contains 10 mg of CyPep-1 and 
corresponding to 14 mg of acetate salt. An additional overfill is included in each vial to ensure that 
the labelled amount of 10 mg of CyPep-1 (corresponding to 14 mg of the acetate salt) can be 
delivered.  
Pembrolizumab is formulated as a 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless 
to slightly yellow solution in single-dose vials.  
CyPep-1 and pembrolizumab will be supplied by Cytovation ASA.  
CyPep-1 and pembrolizumab will be labelled in compliance with the legal requirements of each 
country. The label text will also be translated and/or adjusted, to follow applicable regulatory 
requirements (eg, Clinical Trials Regulation EU No 536/2014 [Annex 6]), national laws in force, 
and in accordance with the local languages. In addition, each label will include storage conditions 
for the drug without the information about the study.  
5.5.2 
Study Drug Preparation and Handling 
The study drugs must be received by a designated person at the study site, handled safely and 
properly, and kept in a secured location to which only the Investigator, Pharmacist, and designated 
assistants have access. Upon receipt of the study drugs, all supplies should be stored according to 
the instructions specified on the study drug labels. See Section 5.5.5 for details of storage 
condition.  
The Pharmacy Manual contains specific instructions for the preparation of CyPep-1 and 
pembrolizumab administration solutions.  
5.5.3 
Study Drug Administration 
The overall study treatment regimen is defined as IT CyPep-1 in combination with IV 
pembrolizumab.  
5.5.3.1 
CyPep-1 administration 
The study Investigator will identify qualified staff who will perform IT injections and this decision 
will therefore be made on a site-by-site basis. The Sponsor will provide training on lesion selection 
and IT injection to Investigators participating in the study as part of the protocol training. 
Lesions appropriate for IT injection will be determined following assessment of procedural and 
operational complexity and risk. While deeper lesions may be targeted, cutaneous lesions that are 
injectable without imaging will be prioritized. Further details regarding selection of tumor lesions 
as well as recommendations for IT injection procedures will be provided to Investigators and staff 
in the Guidance for Intra-tumoral Administration of CyPep-1 study manual. 
Premedication with an antihistamine IV or oral equivalent should be administered approximately 
30 to 60 minutes prior to the first IT dose of CyPep-1. Premedication should be administered prior 

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to subsequent CyPep-1 doses based upon clinical judgment and presence/severity of prior 
reactions. This regimen may be modified based on local treatment standards and guidelines as 
appropriate. Patients should be well hydrated prior to CyPep-1 administration. 
CyPep-1 will be administered Q2W as an IT injection. CyPep-1 will be administered through a 
needle, which should be redirected along multiple tracks to ensure even dispersion of CyPep-1 
throughout the tumor lesion. On the visits that CyPep-1 and pembrolizumab are administered on 
the same day, CyPep-1 is to be administered 30 to 60 minutes after pembrolizumab infusion is 
completed. Following CyPep-1 administration, patients must be observed for 4 hours post injection 
at Cycle 1 Visit 1 and Cycle 2 Visit 1 and 1 hour post injection at Cycle 1 Visit 2 and Cycle 1 
Visit 3 for potential immediate injection-related reactions. Refer to the Guidance for Intra-tumoral 
Administration of CyPep-1 study manual for more details. 
The cumulative maximal injected volume of CyPep-1 will be 4 mL (cumulative maximal dose of 
20 mg at the recommended 5 mg/mL concentration) per treatment day for each patient, and it may 
be divided for injection over 1 to 3 tumor lesions (satellitosis/grouped lesions <1 cm count as 
1 lesion) depending on tumor lesion size; see Table 9. The injected lesions identified at baseline 
should be injected 3 times before selecting new lesions to inject, unless there is a complete 
response or the lesion, by the Investigator¶s assessment, has been adequately treated (eg, reduced 
size and highly inflamed). The volume of CyPep-1 delivered to each injected lesion will be 
determined based on the longest diameter of the lesion. Effort should be made to administer the 
maximum volume of CyPep-1 as planned per lesion size; see Table 9.  
Table 9. 
Approximate Injected CyPep-1 Volume per Lesion Size 
Measured Lesion Diameter (cm) 
Injected Volume (mL) 
0.79 
0.1 
0.80-0.99 
0.2 
1.00-1.24 
0.5 
1.25-1.50 
1.5 
1.51-2.49 
3.0 
2.50-5.00 
4.0 
CyPep-1 4 mL administration may be split into 3 injections (1 injection/lesion) per treatment cycle. 
If the injected lesion(s) attains CR during the Treatment Period, then another lesion (non-injected) 
can be selected for injection (injected lesion) upon discussion with the Sponsor and the Medical 
Monitor.  
IT CyPep-1 treatment is under development and will not be available for treatment of the patients 
after study completion. After participation, patients will continue treatment in accordance with 
clinical practice, ie, as per local guidelines and standard of care. 
5.5.3.2
Pembrolizumab administration 
The dose of pembrolizumab in combination with CyPep-1 will be 400 mg Q6W administered via 
a 30-minute infusion, beginning at Cycle 1 Visit 1. On the visits that CyPep-1 and pembrolizumab 
are administered on the same day, CyPep-1 is to be administered 30 to 60 minutes after
pembrolizumab infusion is completed. Pembrolizumab may be administered up to 3 days before 
or after the scheduled Visit 1 of each cycle from Cycle 2 onward. 
Every effort should be made to ensure the duration of infusion administration will be as close to 
30 minutes as possible. However, given the variability of infusion pumps from study site to study 
The cumulative maximal injected volume of CyPep-1 will be 4 mL (cumulative maximal dose of 
j
y
p
(
20 mg at the recommended 5 mg/mL concentration) per treatment day for each patient, and it may 
g
g
) p
y
p
,
y
be divided for injection over 1 to 3 tumor lesions (satellitosis/grouped lesions <1 cm count as 
j
(
g
p
1 lesion) depending on tumor lesion size; see Table 9. The injected lesions identified at baseline 
)
p
g
;
j
should be injected 3 times before selecting new lesions to inject, unless there is a complete 
j
g
j
,
p
response or the lesion, by the Investigator¶s assessment, has been adequately treated (eg, reduced 
p
, y
g
,
q
y
( g,
size and highly inflamed). The volume of CyPep-1 delivered to each injected lesion will be 
g y
)
y
p
j
determined based on the longest diameter of the lesion. Effort should be made to administer the 
d
g
maximum volume of CyPep-1 as planned per lesion size; see Table 9. 
Table 9. 
Approximate Injected CyPep-1 Volume per Lesion Size 
Measured Lesion Diameter (cm) 
Injected Volume (mL) 
0.79 
0.1 
0.80-0.99 
0.2 
1.00-1.24 
0.5 
1.25-1.50 
1.5 
1.51-2.49 
3.0 
2.50-5.00 
4.0 
CyPep-1 4 mL administration may be split into 3 injections (1 injection/lesion) per treatment cycle. 
y
p
y
p
j
(
j
) p
y
If the injected lesion(s) attains CR during the Treatment Period, then another lesion (non-injected)
j
( )
g
,
(
j
)
can be selected for injection (injected lesion) upon discussion with the Sponsor and the Medical 
Monitor. 
IT CyPep-1 treatment is under development and will not be available for treatment of the patients 
y
p
p
p
after study completion. After participation, patients will continue treatment in accordance with 
y
p
p
p
, p
clinical practice, ie, as per local guidelines and standard of care

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site, a window between -5 and +10 minutes is permitted (ie, the infusion time is 
30 [-5/+10] minutes). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
5.5.3.3 
Dose modification and toxicity management 
CyPep-1 dose modifications are not planned. In the event of CyPep-1-related excessive toxicity, 
administration of CyPep-1 may be delayed for no more than 7 days. Any delay will be per the 
Investigator¶s discretion for the management of a patient with excessive toxicity and may consider 
factors such as recovery from the procedure, scheduling difficulty, or recovery from toxicities. If 
delayed >7 days, then that dose will be omitted at the discretion of the Investigator with the 
approval of the Medical Monitor. After 14 days of delay, consult with the Sponsor. 
CyPep-1 must be permanently discontinued if a patient experiences:  
 A severe systemic hypersensitivity reaction that is uncontrolled with standard management or 
requires high dose steroids; 
 Necrosis, ulcerations, bleeding, or any other serious complication in healthy tissues 
surrounding the injected tumor; or 
 Injected tumor ulcerations that do not show a healing trend in a 3-week period. 
In case of pembrolizumab-related toxicity ( Grade 2 according to the NCI CTCAE v5.0), 
treatment with CyPep-1 will be delayed until a review is completed by the Investigator and 
Medical Monitor. If treatment with CyPep-1 is delayed >7 days, then that dose will be omitted. 
After 14 days of delay, consult with the Sponsor. 
Dose modification and toxicity management for immune-related adverse events associated with 
pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab 
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, 
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, and/or skin biopsy may be included as part of the evaluation. 
Based on the severity of irAEs, pembrolizumab may be withheld or permanently discontinued, and 
corticosteroids may be administered. Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in Table 10. 
Attribution of toxicity  
When study interventions 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 CyPep-1 alone, or to pembrolizumab alone, for AEs listed in Table 10, both 
interventions must be held according to the criteria in Table 10.  

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Holding study interventions  
When study interventions are administered in combination, if the AE is considered 
immune-related, both interventions should be held according to recommended dose modifications. 
Restarting study interventions  
Patients may not have any dose modifications (no change in dose or schedule) of pembrolizumab 
in this study, as described in Table 10.  
If the toxicity does not resolve or the criteria for resuming treatment are not met, the patient must 
be discontinued from all study interventions.  
If the toxicities do resolve and conditions are aligned with what is defined in Table 10, the 
combination of CyPep-1 and pembrolizumab may be restarted at the discretion of the Investigator. 
In these cases where the toxicity is attributed to the combination or to CyPep-1 alone, re-initiation 
of pembrolizumab as a monotherapy may be considered after communication with, and agreement 
by, the Sponsor. 
 
 

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Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
AEs Associated With Pembrolizumab 
General instructions: 
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2.
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 10 mg/day 
within 12 weeks of the last pembrolizumab treatment.  
3.
The corticosteroid taper should begin when the irAE is Grade 1 and continue for at least 4 weeks. 
4.
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreases to Grade 1 after corticosteroid 
taper. 
irAEs 
Toxicity 
Grade (NCI 
CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or 
Other Therapies  
Monitoring and 
Follow-Up  
Pneumonitis 
Grade 2 
Withhold  
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper; and/or 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Monitor patients for signs 
and symptoms of 
pneumonitis. 
Evaluate patients with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
Recurrent 
Grade 2, 3, or 
4  
Permanently 
discontinue 
Diarrhea/colitis  
Grade 2 or 3 
Withhold
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor patients for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood, or 
mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
Patients with Grade 2 
diarrhea, suspecting colitis, 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis.
Patients 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 4 
Permanently 
discontinue 
AST or ALT 
elevation or 
increased 
bilirubin 
Grade 2a 
Withhold
Administer 
corticosteroids (initial 
dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor patients with liver 
function tests (consider 
weekly or more frequently 
until liver enzyme value 
returns to baseline or is 
stable). 
Grade 3b or 4c
Permanently 
discontinue 
Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
y
AEs Associated With Pembrolizumab 
General instructions: 
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other
g
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2.
pp
g
y
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
r
corticosteroid dose is not 10 mg/day 
p
y
within 12 weeks of the last pembrolizumab treatment. 
3.
p
The corticosteroid taper should begin when the irAE is Grade 1 and continue for at least 4 weeks. 
4.
p
g
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreases to Grade 1 after corticosteroid 
p
taper. 
Toxicity y
Grade (NCI 
Action With 
Corticosteroid and/or 
Monitoring and
irAEs 
(
CTCAE v5.0) 
Pembrolizumab 
Other Therapies
g
Follow-Up 
Administer 
Monitor patients for signs
corticosteroids (initial 
p
and symptoms of
(
dose of 1 to 2 mg/kg 
y p
pneumonitis.
g g
prednisone or equivalent)
p
Evaluate patients with 
Grade 2 
Withhold 
p
q
)
followed by taper; and/or
p
suspected pneumonitis with 
Recurrent 
y
p
Add prophylactic
p
p
radiographic imaging and
Grade 2, 3, or 
Permanently 
p
p y
antibiotics for 
g p
g g
initiate corticosteroid 
Pneumonitis 
4 
y
discontinue 
opportunistic infections. 
treatment. 
Monitor patients for signs
p
and symptoms of 
y p
enterocolitis (ie, diarrhea, 
( ,
,
abdominal pain, blood, or
p
,
mucus in stool with or 
without fever) and of bowel 
Grade 2 or 3 
Withhold
)
perforation (ie, peritoneal
p
( , p
signs and ileus). 
g
)
Patients with Grade 2 
diarrhea, suspecting colitis, 
,
p
g
should consider GI 
consultation and 
performing endoscopy to 
p
g
rule out colitis.
Patients with 
diarrhea/colitis should be 
advised to drink liberal 
Administer 
quantities of clear fluids. If
corticosteroids (initial 
q
sufficient oral fluid intake 
(
dose of 1 to 2 mg/kg 
is not feasible, fluid and
Recurrent 
Permanently 
g g
prednisone or equivalent)
,
electrolytes should be 
Diarrhea/colitis 
Grade 3 or 4 
y
discontinue 
p
q
followed by taper. 
y
substituted via IV infusion. 
y
Grade 
AST or ALT 
elevation or 
increased 
bilirubin 
y
Administer 
corticosteroids (initial 
(
dose of 0.5 to 1 mg/kg 
g g
g g
prednisone or equivalent)
2a
Withhold
p
q
followed by taper. 
r 
Monitor patients with liver
p
Administer 
y
r 
p
function tests (consider 
corticosteroids (initial 
(
weekly or more frequently 
y
q
(
dose of 1 to 2 mg/kg 
y
q
until liver enzyme value
y
Permanently 
g g
prednisone or equivalent)
y
returns to baseline or is 
Grade 3b or 4c
y
discontinue 
p
q
followed by taper
stable). 

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Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
AEs Associated With Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
(NCI 
CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or 
Other Therapies  
Monitoring and Follow-Up  
T1DM or 
hyperglycemia 
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withholdd
Initiate insulin 
replacement therapy 
for patients with 
T1DM; and/or 
Administer 
anti-hyperglycemic in 
patients with 
hyperglycemia. 
Monitor patients for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor patients for signs 
and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
Withhold or 
permanently 
discontinued
Hyperthyroidism 
Grade 2 
Continue 
Treat with 
non-selective 
-blockers (eg, 
propranolol) or 
thionamides as 
appropriate. 
Monitor for signs and 
symptoms of thyroid 
disorders.
Grade 3 or 4 
Withhold or 
permanently 
discontinued
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per 
standard of care. 
Monitor patients for signs 
and symptoms of thyroid 
disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 2 
Withhold 
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) followed 
by taper. 
Monitor patients for 
changes of renal function. 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
toxicities
Grade 2 
Withhold
Based on severity of 
AE administer 
corticosteroids. 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes. 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 2, 3, or 4 
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
Based on severity of 
AE administer 
corticosteroids. 
Ensure adequate evaluation 
to confirm etiology or 
exclude other causes. 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
y
g
AEs Associated With Pembrolizumab (Continued)
Toxicity Grade 
y
(NCI 
Action With 
Corticosteroid and/or 
irAEs 
(
CTCAE v5.0) 
Pembrolizumab 
Other Therapies
Monitoring and Follow-Up 
Initiate insulin 
New onset 
replacement therapy
T1DM or 
p
for patients with
Grade 3 or 4 
p
T1DM; and/or 
hyperglycemia 
;
Administer 
Monitor patients for 
yp g y
associated with 
anti-hyperglycemic in 
p
hyperglycemia or other
T1DM or 
evidence of 
yp g y
patients with
yp g y
signs and symptoms of
hyper
y
glycemia 
-cell failure 
Withholdd
p
hyper
y
glycemia. 
g
diabetes. 
Administer 
Monitor patients for signs
Grade 2 
Withhold
corticosteroids and 
p
and symptoms of 
Withhold or 
initiate hormonal 
y p
hypophysitis (including 
permanently
replacements as 
yp p y
(
g
hypopituitarism and adrenal 
Hypoph
y
ysitis 
Grade 3 or 4 
p
y
discontinued
p
clinically indicated. 
yp p
insufficiency). 
Treat with 
non-selective 
Grade 2 
Continue 
-blockers (eg, 
Withhold or 
( g,
propranolol) or
Monitor for signs and 
permanently
p
p
)
thionamides as 
g
symptoms of thyroid
Hyperth
y
yroidism 
Grade 3 or 4 
p
y
discontinued
appropriate. 
y p
disorders.
pp
p
Initiate thyroid 
y
replacement hormones
p
(eg, levothyroxine or 
Monitor patients for signs
( g,
y
liothyronine) per 
p
g
and symptoms of thyroid
Hypoth
y
yroidism 
Grade 2, 3, or 4 
Continue 
y
) p
standard of care. 
y p
disorders. 
p
y
y
Nephritis:
p
grading 
Grade 2 
Withhold
Administer 
g
g
according to
corticosteroids 
g
increased 
(prednisone 
creatinine or 
(p
1 to 2 mg/kg or 
acute kidney 
Permanently 
g g
equivalent) followed 
Monitor patients for 
injn ury
r
Grade 3 or 4 
y
discontinue 
q
by taper. 
p
changes of renal function. 
Grade 2 
Withhold
Based on severity of
Ensure adequate evaluation 
Neurological 
Permanently 
AE administer 
q
to confirm etiology and/or 
g
toxicities
Grade 3 or 4 
y
discontinue 
corticosteroids. 
gy
exclude other causes. 
Based on severity of
Ensure adequate evaluation 
Permanently 
AE administer 
q
to confirm etiology and/or 
Myocarditis 
Grade 2, 3, or 4 
y
discontinue 
corticosteroids. 
gy
exclude other causes. 
Suspected SJS, 
p
TEN, or 
,
DRESS 
Withhold
Exfoliative 
Based on severity of
Ensure adequate evaluation 
dermatologic 
AE administer 
q
to confirm etiology or 
g
conditions 
corticosteroids. 
gy
exclude other cause
Confirmed SJS,
TEN, or 
Permanently 
,
DRESS 
y 
discontinue 
y

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Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
AEs Associated With Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
(NCI 
CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or 
Other Therapies  
Monitoring and Follow-Up  
All other irAEs 
Persistent 
Grade 2 
Withhold
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 
evente
Recurrent 
Grade 3 or 4  
Permanently 
discontinue 
Note: Non-irAEs will be managed as appropriate, following clinical practice recommendations. 
a.
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline if baseline abnormal; bilirubin: >1.5 to 3.0 × ULN 
if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal.
b.
AST/ALT: >5.0 to 20.0 × ULN if baseline normal; >5.0 to 20.0 × baseline if baseline abnormal; bilirubin: >3.0 to 
10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal. 
c.
AST/ALT: >20.0 × ULN if baseline normal; >20.0 × baseline if baseline abnormal; bilirubin: >10.0 × ULN if baseline 
normal; >10.0 × baseline if baseline abnormal. 
d.
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the Investigator or treating 
physician. If control achieved or Grade 2, pembrolizumab may be resumed. 
e.
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; CTCAE = Common Terminology 
Criteria for Adverse Events; DRESS = Drug Rash with Eosinophilia and Systemic Symptom; GI = gastrointestinal; 
irAE = immune-related adverse event; IV = intravenous; NCI = National Cancer Institute; SJS = Stevens-Johnson Syndrome; 
T1DM = type 1 diabetes mellitus; TEN = Toxic Epidermal Necrolysis; ULN = upper limit of normal; v = version. 
Dose modification and toxicity management of infusion reactions related to 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. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reactions 
are provided in Table 11. 
Table 10. Dose Modification and Toxicity Management Guidelines for Immune-Related 
y
g
AEs Associated With Pembrolizumab (Continued)
Toxicity Grade 
y
(NCI 
Action With 
Corticosteroid and/or 
irAEs 
(
CTCAE v5.0) 
Pembrolizumab 
Other Therapies 
Monitoring and Follow-Up 
Persistent 
Grade 2 
Withhold
Withhold or 
discontinue 
based on the 
Grade 3 
evente
Based on severity of
Ensure adequate evaluation 
Recurrent 
Permanently 
AE administer 
q
to confirm etiology or 
All other irAEs 
Grade 3 or 4 
y
discontinue 
corticosteroids. 
gy
exclude other causes. 
Note: Non-irAEs will be managed as appropriate, following clinical practice recommendations. 
a.
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline if baseline abnormal; bilirubin: >1.5 to 3.0 × ULN
;
if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal.
b.
;
AST/ALT: >5.0 to 20.0 × ULN if baseline normal; >5.0 to 20.0 × baseline if baseline abnormal; bilirubin: >3.0 to
;
10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal. 
c.
;
AST/ALT: >20.0 × ULN if baseline normal; >20.0 × baseline if baseline abnormal; bilirubi
f
n: >10.0 × ULN if baseline 
;
normal; >10.0 × baseline if baseline abnormal. 
d.
;
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the Investigator or treating 
p
physician. If control achieved or 
y
p
Grade 2, pembrolizumab may be resumed. 
e.
p y
, p
y
Events that require discontinuation include, but are not limited to, encephalitis and other clinically important irAEs (eg,
q
vasculitis and sclerosing cholangitis). 
g
g
)
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology 
;
;
p
;
gy
Criteria for Adverse Events; DRESS = Drug Rash with Eosinophilia and Systemic Symptom; GI = gastrointestinal; 
;
g
p
y
y p
;
g
;
irAE = immune-related adverse event; IV = intravenous; NCI = National Cancer Institute; SJS = Stevens-Johnson Syndrome;
;
;
;
T1DM = type 1 diabetes mellitus; TEN = Toxic Epidermal Necrolysis; ULN = upper limit of normal; v = version. 
Dose modification and toxicity management of infusion reactions related to pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
y
g
,
g
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
yp
y
p y
g
y p
y
p
g
y
g
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
f
g
y
p
y
p
modification and toxicity management guidelines on pembrolizumab-associated infusion reactions 
y
are provided in Table 11

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Table 11. Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically indicated until 
the patient is deemed medically stable in the opinion of the 
Investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for 24 hours 
Stop Infusion; 
Additional appropriate medical therapy may include, 
but is not limited to the following: 
o
IV fluids; 
o
Antihistamines; 
o
NSAIDs; 
o
Acetaminophen; 
o
Narcotics; 
o
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the Investigator; and 
o
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/hour to 50 mL/hour). Otherwise, 
dosing will be held until symptoms are 
resolved, and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity, despite adequate 
premedication, should be permanently discontinued from 
further study drug treatment. 
Patient may be 
premedicated 
1.5 hours 
(±30 minutes) prior 
to infusion of study 
intervention with 
diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine) or 
acetaminophen 
500 to 1000 mg po 
(or equivalent dose 
of analgesic). 
Grade 3 
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Grade 4 
Life-threatening; 
pressor or ventilator 
support indicated
Stop Infusion; 
Additional appropriate medical therapy may include, 
but is not limited to the following: 
o
Epinephrine**; 
o
IV fluids; 
o
Antihistamines; 
o
NSAIDs; 
o
Acetaminophen; 
o
Narcotics; 
o
Oxygen; 
o
Pressors; 
o
Corticosteroids; 
o
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the Investigator; and 
o
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Patient is permanently discontinued from further study drug 
treatment. 
No subsequent 
dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov. 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous(ly); NCI = National Cancer Institute; 
NSAID = nonsteroidal anti-inflammatory drug; po = oral(ly); v = version. 
Table 11. Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines 
Premedication at 
Subsequent 
NCI CTCAE Grade 
Treatment 
q
Dosing 
Grade 1 
Mild reaction; infusion 
;
interruption not 
Increase monitoring of vital signs as medically indicated until 
p
indicated; intervention
g
g
y
the patient is deemed medically stable in the opinion of the 
;
not indicated
p
Investigator. 
None 
Stop Infusion; 
p
;
Additional appropriate medical therapy may include, 
pp
p
but is not limited to the following: 
IV fluids; 
o
;
Antihistamines;
o
NSAIDs;
o
;
Acetaminophen;
o
Narcotics; 
Patient may be 
o
;
Increase monitoring of vital signs as medically
y
premedicated
o
g
g
y
indicated until the patient is deemed medically 
p
1.5 hours 
Grade 2 
p
stable in the opinion of the Investigator; and 
(±30 minutes) prior
Requires therapy or 
p
g
;
If symptoms resolve within 1 hour of stopping 
(
) p
to infusion of study 
o
q
py
infusion interruption 
y p
pp g
drug infusion, the infusion may be restarted at
intervention with 
p
but responds promptly 
g
,
y
50% of the original infusion rate (eg, from 
diphenhydramine 
p
p
to symptomatic
g
( g
g
( g,
100 mL/hour to 50 mL/hour). Otherwise, 
p
y
p
y
50 mg po (or 
y p
treatment (eg, 
)
dosing will be held until symptoms are
g p (
equivalent dose of
( g,
antihistamines, 
g
y p
resolved, and the patient should be 
q
antihistamine) or 
,
NSAIDs, narcotics, IV 
,
p
premedicated for the next scheduled dose. 
)
acetaminophen 
,
,
fluids); prophylactic 
p
Patients who develop Grade 2 toxicity, despite adequate 
p
500 to 1000 mg po 
); p
p y
medications indicated 
p
y,
p
q
premedication, should be permanently discontinued from 
g p
(or equivalent dose
for 24 hours 
p
,
p
further study drug treatment. 
(
q
of analgesic). 
Stop Infusion; 
Grade 3 
p
Additional appropriate medical therapy may include, 
Prolonged (ie, not 
pp
p
but is not limited to the following: 
g
( ,
rapidly responsive to
Epinephrine**; 
o
p
y
p
symptomatic 
p
p
IV fluids; 
o
y p
medication and/or brief 
;
Antihistamines;
o
interruption of 
NSAIDs;
o
p
infusion); recurrence 
;
Acetaminophen;
o
);
of symptoms following 
Narcotics; 
o
y p
initial improvement;
Oxygen; 
o
p
hospitalization 
yg
;
Pressors; 
o
p
indicated for other 
;
Corticosteroids; 
o
clinical sequelae (eg, 
;
Increase monitoring of vital signs as medically
o
q
(
renal impairment, 
g
g
y
indicated until the patient is deemed medically 
p
,
pulmonary infiltrates) 
p
stable in the opinion of the Investigator; and
p
Hospitalization may be indicated. 
o
Grade 4 
p
y
**In cases of anaphylaxis, epinephrine should
Life-threatening; 
p y
be used immediately. 
g;
pressor or ventilator 
Patient is 
p
support indicated
permanently discontinued from further study drug 
y
No subsequent
p
treatment. 
dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of
pp
p
q p
p y
y
drug administration. For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov. 
g
, p
p
p
g
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous(ly); NCI = National Cancer Institute;
gy
;
NSAID = nonsteroidal anti-inflammatory
r dru
y
g; po = oral(ly); v = version.

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Other allowed dose interruptions for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 6 weeks or 42 days (for Q6W dosing) of the 
originally scheduled dose and within 84 days (for Q6W dosing) of the previously administered 
dose, unless otherwise discussed with the Sponsor. The reason for interruption is to be documented 
in the patient¶s study record. If pembrolizumab is interrupted, CyPep-1 can continue to be 
administered at a Q2W schedule as described in the Schedule of Assessments (Appendix A). 
5.5.3.4
Overdose 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
No specific information is available on the treatment of pembrolizumab overdose. In the event of 
an overdose, the patient should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated. 
5.5.4
Treatment Compliance 
Administration of IT CyPep-1 and administration of IV pembrolizumab will be done in a 
hospitalized environment by trained study personnel. Treatment compliance will be determined by 
documentation of CyPep-1 and pembrolizumab dispensation and administration, including, but 
not limited to, the batch numbers of CyPep-1 and pembrolizumab, the date and time of preparation, 
date and time of administration, and signatures of designated study site staff preparing and 
administering IT CyPep-1 and IV pembrolizumab.  
In the event a planned CyPep-1 administration is missed, the treatment should be given as soon as 
possible but no less than 7 days from the next planned administration. 
Any dosing deviations (eg, missed, delayed, incomplete, or interrupted doses) will be documented 
on the appropriate eCRF. 
5.5.5
Storage and Accountability 
CyPep-1 should be stored at 5 ±3°C (41 ±5.4°F), protected from light. CyPep-1 may be kept 
outside the storage conditions at temperatures up to 25°C (77°F) for up to 3 days to cover 
short-term temperature excursions (eg, during shipping, labelling, and handling).  
Pembrolizumab should be used, handled, and stored in line with institutional guidelines and the 
IB.23  
In accordance with regulatory requirements, the Investigator or designated study site personnel 
must document the amount of study drugs administered to patients, the amount received from and 
returned to the Sponsor (or representative) when applicable, as well as maintain a temperature log 
to document temperature conditions during storage. Study drug accountability records must be 
maintained throughout the course of the study. Discrepancies are to be reconciled or resolved. 
Procedures for final disposition of unused study drugs will be provided in the Pharmacy Manual. 
The study drugs must be used only as directed in the protocol and for patients enrolled in this study 
only.  
Other allowed dose interruptions for pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as
y
p
,
medical or surgical events and/or unforeseen circumstances not rela
n
ted to study intervention. 
g
y
However, study intervention is to be restarted within 6 weeks or 42 days (for Q6W dosing) of the 
,
y
y (
Q
g)
originally scheduled dose and within 84 days (for Q6W dosing) of the previously administered 
g
y
y (
Q
g)
p
y
dose, unless otherwise discussed with the Sponsor. The reason for interruption is to be documented
,
p
p
in the patient¶s study record. If pembrolizumab is interrupted, CyPep-1 can continue to b

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5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
The prophylactic use of systemic corticosteroids is not permitted; for exceptions, see Section 5.6.2.  
Medications or vaccinations specifically prohibited in the Exclusion Criteria (Section 4.2) are not 
allowed during the study.  
The following treatments must not be administered during the study: 
 Immunotherapy not specified in this protocol, immunosuppressive drugs, or other 
investigational agents other than CyPep-1 or pembrolizumab within 30 days prior to the first 
dose of CyPep-1. Steroids are only allowed per criteria described in Section 5.6.2;  
 Chronic concurrent therapy with antibiotics within 2 weeks before and during the Treatment 
Period. Antibiotics for new active infection (ie, AEs/SAEs) will be allowed during the 
Treatment Period; 
 Herbal and local remedies;  
Note: Use of cannabis  or cannabidiol containing products are only allowed if they are 
considered legal and used according to local regulations.  
 Any other anti-neoplastic systemic chemotherapy, biological treatment, or concurrent 
anti-cancer treatment or chemotherapy not specified in this protocol; 
Note: Use of denosumab for patients with bone metastasis is allowed.  
 Radiation therapy; and 
Note: Palliative short course, limited-field radiotherapy (ie, 10 fractions and 30% bone 
marrow involvement or per institutional standard) may be administered during the study only 
to symptomatic lesions that are not categorized as target or injected. 
 Live or live attenuated COVID-19 vaccines. 
Patients must not have a major surgical procedure within 14 days prior to the first dose of CyPep-1. 
5.6.2 
Restricted Medications and/or Procedures 
COVID-19 vaccination is expected to elicit systemic post-vaccination symptoms, such as fatigue, 
fever, chills, headache, myalgias, and hypersensitivity in patients. The systemic side effects are 
dependent upon each different COVID-19 vaccine but tend to occur within 2 to 3 days of the 
vaccine and may be more pronounced with the second dose, where applicable. Given limited data, 
the possible interactions between CyPep-1, pembrolizumab, and COVID-19 vaccines are unknown 
at this time. Reference should be given to the summary of product characteristics/package inserts 
for these products, current literature, and expert consensus recommendations when considering the 
risk/benefit for individual patients. Therefore, COVID-19 vaccines are only permitted with 
documentation of the date of the vaccine if the last dose of vaccine was administered >14 days 
prior to the first dose of CyPep-1. The COVID-19 booster vaccine must be administered at least 
14 days prior to the first dose of CyPep-1 and is not allowed during the first 3 months of the 
Treatment Period. Live or live attenuated COVID-19 vaccines must not be administered during 
the study.  

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Patients who are on anti-coagulants must be able to switch to a low molecular weight heparin or 
equivalent prior to Cycle 1 Day 1 and continue during the Treatment Period. 
Administration of steroids through a route known to result in a minimal systemic exposure (topical 
[only on areas outside the injected lesions], intranasal, intro-ocular, or inhalation) is acceptable at 
the lowest possible dose.  
In the absence of active autoimmune disease, systemic glucocorticoids are permitted only for the 
following purposes: 
 To treat an AE or SAE; 
 As needed for the prevention of emesis; 
 As premedication for IV contrast allergies; 
 For short-term oral or IV use in doses >10 mg/day prednisone equivalent for Chronic 
Obstructive Pulmonary Disease (COPD) exacerbations;  
 For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent; 
 For intraarticular joint use; and 
 For inhalation in the management of asthma, COPD, or seasonal allergy.  
5.6.3 
Allowed Medications and/or Procedures 
Replacement therapies (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency) are allowed. 
Vitamin and mineral supplements are allowed during the study. 
Seasonal flu vaccines that do not contain live vaccine are permitted. 
Premedication with an antihistamine IV or oral equivalent should be administered approximately 
30 to 60 minutes prior to the first IT dose of CyPep-1. Premedication should be administered prior 
to subsequent CyPep-1 doses based upon clinical judgment and presence/severity of prior 
reactions. This regimen may be modified based on local treatment standards and guidelines as 
appropriate. 
At the discretion of the Investigator, any concomitant medication or therapy deemed necessary for 
the welfare of the patient during the study, eg, for the treatment of AEs may be given. It is the 
responsibility of the Investigator to ensure that these medications or therapies are documented in 
the Concomitant Medication page of the eCRF.  
Medications may be administered due to anticipated adverse reactions or anticipated emergency 
situations.  
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. 
5.6.4 
Documentation of Prior and Concomitant Medication Use 
Medications and therapies taken within 28 days prior to the Screening Visit until the Safety 
Follow-up Visit will be recorded in the eCRF. All concomitant medications and changes in 
concomitant medications (including vitamins and minerals) will be recorded throughout the course 

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of the study in the eCRFs. Information recorded will include the medication name, dose, duration, 
and reason for taking each medication.  
Medications and therapies taken specifically for the management of solid tumors prior to signing 
the ICF will be recorded on the Prior Medications and Therapies page of the eCRF. 
All medications, including prescription and over-the-counter drugs; vitamins and minerals; and IV 
medications, fluids, and therapies used during the study, in addition to the study treatment 
(CyPep-1 and/or pembrolizumab), will be considered concomitant. All concomitant medications 
administered during SAEs or AEs of clinical interest (AECIs) are also to be recorded. The 
following concomitant medications or therapies are of clinical interest: 
 Palliative medications;  
 Medication for the treatment of infections, including prophylactic or pre-emptive use of 
anti-infective medication; 
 Medication for the treatment of other reported AEs; and 
 Prophylactic use of immunosuppressive medication. 
5.6.5 
Dietary Restrictions 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 

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6 
STUDY PROCEDURES 
Study procedures will follow the Schedule of Assessments (Appendix A).  
This study protocol includes contingency measures to manage disruptions due to COVID-19 
control measures, including modifications to visit schedules and procedures specific to situations 
where COVID-19 is impacting study conduct. See Section 3.1.4 for details of COVID-19 
contingency measures. In the absence of a COVID-19 impact, it is expected that Investigators and 
patients follow the protocol requirements as set forth. 

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7 
EFFICACY ASSESSMENTS 
7.1 
Local Measurement of Tumor Lesions 
Local tumor measurements of accessible target tumor lesion(s) will be made at screening, and then 
Q8W (±3 days), according to RECIST v1.1, until occurrence of confirmed PD as defined by 
iRECIST (Appendix D), start of a new anti-cancer treatment, pregnancy, death, withdrawal of 
consent, or end of study (approximately 26 months after the start of treatment).  
Tumor assessment for cutaneous lesions will be made by caliper and color digital photography 
using a ruler held flush to the skin next to the longest diameter of the lesion to indicate the size of 
the lesion. As per RECIST v1.1, lesions 10 mm identified as target lesions require measurement 
by clinical exam with caliper. Lesions that cannot be accurately measured with calipers should be 
recorded as non-measurable. For subcutaneous lesions, itRECIST permits an ultrasound 
measurement if no other lesions are available for quantitative assessment. For injected lesions 
under ultrasound control, an ultrasound-based measurement must be performed prior to each 
injection. Ultrasounds and photography will be collected and held centrally for potential central 
radiographic review. 
Lesion(s) that disappear during the Treatment Period will be evaluated during the Follow-up 
Period. 
7.2 
Radiological Assessment 
A baseline radiology assessment will be performed within 4 weeks prior to Cycle 1 Visit 1 to 
identify injected lesions and non-injected lesions and these lesions will be assessed according to 
RECIST v1.1. Subsequent radiological assessments will be performed Q8W (±3 days) after the 
first dose of CyPep-1, according to RECIST v1.1, until the occurrence of confirmed PD as defined 
by iRECIST (Appendix D), start of a new anti-cancer treatment, pregnancy, death, withdrawal of 
consent, or end of study (approximately 26 months after the start of treatment). Tumor scans may 
be performed more frequently if clinically indicated. MRI or CT are the preferred scanning 
procedures to be used in this study. Selection of either MRI or CT should be based on individual 
patient considerations and local regulations and is at the Investigator¶s discretion. Once selected 
for each patient, the same scanning procedure should be used consistently at all remaining visits. 
Scans will be collected and held centrally for potential central radiologic review. 
Scan timing should follow calendar days and should not be adjusted for delays in cycle starts. 
A confirmatory radiological assessment is required 4 weeks after an initial radiological scan 
leading to an assessment of PD. If the PD is confirmed, the initial assessment of PD will be 
considered as the ³first documented PD.´ If PD is not confirmed, the first measured PD will be 
disregarded and assessments should continue as per protocol (ie, the next radiological assessment 
will be performed after an 8-week interval).  
If a patient discontinues study treatment without documented disease progression, every effort 
should be made to monitor disease status by continuing tumor scans Q8W from start of study 
treatment. Scans will be continued until occurrence of confirmed PD as defined by iRECIST 
(Appendix D), start of a new anti-cancer treatment, pregnancy, death, withdrawal of consent, or 
end of study (approximately 26 months after the start of treatment).  

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7.3 
Tumor Biopsy 
Tumor biopsy will be obtained from the identified injected and, whenever available, from the 
identified non-injected lesions at screening. A stored sample may be used if collected within 
90 days prior to screening. At Cycle 1 Visit 4 (±3 days), the same lesion(s) will be used for 
post-treatment biopsy sampling. 
Tumor material will be processed and sent for analysis as described in the Laboratory Manual. 
Tumor material of all patients will be used for analysis. No tumor sample will be obtained if a 
tumor is inaccessible, there is not enough tumor tissue due to shrinkage, or if the biopsy is not in 
the patient¶s best interest. 
Tumor tissue staining will be performed provided there is access to sufficient tissue 
(formalin-fixed paraffin-embedded) post-hoc, batch-wise, during the study or at the end of the 
study and from the most recent available tissue. Tumor tissue will be stained at a central laboratory 
using immunohistochemistry/immunofluorescence in order to determine T cell infiltration and 
characteristics of tumor tissue. Additional staining for other factors based on emerging scientific 
understanding of the IT CyPep-1 therapy may also be performed. 
Additional analyses (eg, tumor mutational burden) may be performed according to the 
Investigator¶s or Sponsor¶s decision. 
7.4 
Pharmacokinetic Sampling 
Blood samples from the first 6 patients enrolled in the study will be collected for PK analyses. 
During Cycle 1 Day 15, the plasma concentration time profile of CyPep-1 will be evaluated and, 
if detectable plasma drug levels are identified, the derived PK parameters will be assessed 
including, AUC, Cmax, Tmax, systemic clearance, t½, and volume of distribution. 
Samples will be collected pre-dose and 15 minutes ( 5 minutes), 30 minutes ( 5 minutes), 1 hour 
( 15 minutes), 2 hours ( 15 minutes), and 4 hours ( 30 minutes) post-dose on Cycle 1 Day 15. 
Collection, processing, storage, and shipping of PK blood samples are described in the Laboratory 
Manual (including specific details for the blood collection tubes). 

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8 
SAFETY ASSESSMENTS 
Safety will be assessed by physical examinations, vital signs, 12-lead ECGs, ECOG performance 
status (Appendix C), laboratory evaluations, and AEs (as defined by NCI CTCAE v5.0; see 
Section 8.1.3) as indicated in the Schedule of Assessments (Appendix A). Additional assessments 
may be performed as clinically indicated.  
Patients will be monitored for DLTs for confirmation of the CyPep-1 dose of 20 mg Q2W in 
combination with pembrolizumab 400 mg Q6W; see Section 3.1.1.1. 
Safety will be monitored in conjunction with the DMC and as per DMC charter.  
8.1 
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 from the 
time of signing the ICF until 30 days after the last dose of study treatment. All AEs that are 
considered serious, from the time of signing the ICF until 90 days (30 days if patients initiate new 
anti-cancer therapy) after the last dose of study treatment, will also be monitored and documented. 
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 treatment/procedure. Beginning at screening, 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.  
Any medical condition already present prior to signing of the ICF 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, ECG) findings that are 
detected during the study or are present prior to signing the ICF 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 

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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 drugs is required as a result of the abnormality; or 
 Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. ³Responses´ 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. 
8.1.2 
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 CyPep-1, the reference safety 
information is included in Section 5.4.1 of the IB currently in force.15 The reference safety 
information will be reviewed yearly and the periodicity of the review will be harmonized with the 
reporting period of the Development Safety Update Report. For pembrolizumab, the reference 
safety information is included in the IB.23 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE, and will also categorize each AE 
as to its potential relationship to study drugs using the categories of yes or no. 
Assessment of severity 
The severity of all AEs should be graded according to the NCI CTCAE v5.0. For those AE terms 
not listed in the NCI CTCAE, the following grading system should be used: 
 NCI CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated; 
 NCI CTCAE Grade 2: Moderate; minimal local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living; 
 NCI 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; 
 NCI CTCAE Grade 4: Life-threatening consequences; urgent intervention indicated; and 
 NCI CTCAE Grade 5: Death related to the AE. 

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Causality assessment 
The relationship of an AE to the administration of the study drugs 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 drugs and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc) is suspected. 
 Yes (possibly, probably, or definitely related) ± The time course between the administration of 
study drugs 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 drugs. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
The following factors should also be considered: 
 The temporal sequence from study drugs administration- 
The event should occur after the study drugs are given. The length of time from study drugs¶ 
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 drugs- 
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 drugs- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drugs should be considered. 

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8.1.4 
Adverse Events of Clinical Interest 
Selected non-serious AEs and SAEs are also known as AECIs and must be reported to the Sponsor 
within 24 hours of the Investigator¶s awareness. 
AECIs for this study include the following:  
 An overdose of pembrolizumab, as defined in Section 5.5.3.4; and 
 An elevated AST or ALT laboratory value that is greater than or equal to 3 times the ULN 
(greater than 5 times the ULN for patients with liver metastases), an elevated total bilirubin 
laboratory value that is greater than or equal to twice the ULN, and, at the same time, an 
alkaline phosphatase laboratory value that is less than twice the ULN, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing. 
Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The study site guidance for assessment and follow-up 
of these criteria can be made available. It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria noted 
above. In these cases, the decision to proceed with additional evaluation will be made through 
consultation between the study Investigators and the Sponsor Clinical Director. However, 
abnormalities of liver blood tests that do not meet the criteria noted above are not AECIs for 
this study. 
8.2 
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; 
Note: Death due to tumor-related symptoms or tumor progression will not be recorded as an 
SAE under this criterion.  
 A life-threatening AE; 
Note: An AE or adverse reaction is considered ³life-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 an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, elective treatment of a pre-existing condition 
that did not worsen from baseline, or hospitalization due to tumor-related symptoms or tumor 
progression. 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.  

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 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; however, when a patient dies from the progression of underlying cancer, the event 
will be captured as an outcome on an eCRF for death due to disease progression. Diagnosis of 
progression of disease or hospitalization due to signs and symptoms of disease progression 
alone should not be reported as an SAE. 
8.3 
Serious Adverse Event Reporting  Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of signing the ICF until 90 days (30 days if patients initiate new 
anti-cancer therapy) after the last dose of study treatment must be reported to Medpace Clinical 
Safety within 24 hours of the knowledge of the occurrence. 
Any SAE brought to the attention of the Investigator at any time outside of the time period 
specified above must be reported immediately, or within 24 hours of the knowledge of the 
occurrence, to Medpace Clinical Safety or the Sponsor/designee if the event is considered to be 
drug-related. 
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 8.6) 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. 
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 
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it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
8.4 
Pregnancy Reporting 
If a patient becomes pregnant during the study or within 120 days (30 days if initiates new 
anti-cancer therapy) after the last dose of study treatment, the Investigator is to stop dosing with 
study drugs immediately. Early termination 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/study site the Exposure In Utero (EIU) form for completion. The 
Investigator/study site must complete the EIU form and fax/email it back to Medpace Clinical 
Safety.  
All exposures during breastfeeding, during the study or within 120 days (30 days if initiates new 
anti-cancer therapy) after the last dose of study treatment, must be reported by the Investigator to 
Medpace Clinical Safety as described above. 
If the female partner of a male patient becomes pregnant while the patient is receiving study drugs 
or within 120 days (30 days if initiates new anti-cancer therapy) after the last dose of study 
treatment, the Investigator should notify Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. 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. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about 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 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, and to the Central 
Ethics Committee 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. 
Listings of cases related to pembrolizumab will be included in the Development Safety Update 
Report. 

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8.6
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 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 situations reports should 
be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line ± United States: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
Medpace SAE reporting line ± Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
Email: medpace-safetynotification@medpace.com 
Safety Contact Information: Medpace Clinical Safety 
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Medpace SAE reporting line ± United States: 
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Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3
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Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
Medpace SAE reporting line ± Europe:
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Telephone: +49 89 89 55 718 44 
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Fax: +49 89 89 55 718 104 
Email: medpace-safetynotification@medpace.com 

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8.7 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will include chemistry, hematology, coagulation, and urinalysis 
parameters from collection of blood and urine samples as indicated in the Schedule of Assessments 
(Appendix A). See Appendix B for a list of clinal laboratory analytes.  
All blood and urine samples will be collected before dosing at dosing visits and can be collected 
up to 72 hours prior to each scheduled dosing visit in order to have the results (of at least chemistry, 
hemoglobin, white blood cell count, platelets, PT/INR, and aPTT) available on the visit day prior 
to dosing. If there are no normal ranges available for PT, INR may be used instead of PT.  
Creatinine clearance will only be estimated at screening using the Chronic Kidney Disease 
Epidemiology Collaboration formula. 
Urinalysis will be performed using gross (dipstick) urine examination. Midstream, clean-catch 
urine specimens will be collected for dipstick analysis. 
Assessments completed at screening within 72 hours prior to the first CyPep-1 administration do 
not need to be repeated at Cycle 1 Visit 1. Unless otherwise noted, samples will be processed, 
analyzed, and reported locally.  
If the Investigator (or qualified designee) encounters an abnormal finding, the Investigator should 
indicate whether the finding is clinically significant or not. Any clinical abnormalities that are 
considered to be clinically significant are recorded as AEs and need to be followed until resolution. 
8.8 
Vital Signs 
Vital signs will be measured in the supine position after at least a 10-minute rest at screening, 
Visit 1 of each dosing cycle, the EoT Visit, and the Safety Follow-up Visit. At dosing visits, vital 
signs will be assessed before dosing (after ECG assessment) and at 15 minutes (±5 minutes), 
30 minutes (±5 minutes), and 1 hour (±10 minutes) after dosing. The following variables will be 
measured: 
 Systolic and diastolic blood pressure (mm/Hg); 
 Pulse rate (beats per minute); and 
 Temperature ( C). 
All blood pressure measurements require the use of a completely automated device on the same 
arm at each measurement. The same type of automated device is to be used for all assessments, at 
least for the same patient. The automated device must be calibrated annually. 
Body temperature will be measured in a consistent manner throughout the study. Continuous 
oxygen monitoring will be performed if the patient has respiratory problems. 
8.9 
Electrocardiograms 
A standard single 12-lead ECG will be collected at screening, at Cycle 1 Visit 1, Cycle 1 Visit 2, 
and at Visit 1 of each subsequent cycle.  
A computerized ECG device will be used after the patient has rested at least 10 minutes in the 
supine position (ie, lying horizontally with the face and torso facing up). Patient must remain 
supine but awake during ECG collection.  

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The following parameters will be automatically calculated by the ECG device: heart rate, PR/PQ 
interval, QRS interval, and QT interval (uncorrected).  
All ECGs will be evaluated by a physician to provide immediate safety monitoring, an ECG 
diagnosis, and an overall assessment (including clinical relevance). Corrected QT intervals will be 
derived in addition for data evaluation. 
ECGs should be collected prior to any invasive procedures (eg, study treatment administration and 
blood sample collection) and any scheduled vital signs measurements.  
8.10 
Height, Weight, and Physical Examinations 
Height will only be recorded at the Screening Visit and will be recorded in centimeters.  
Weight will be recorded in kilograms at each study site visit. At dosing visits, weight will be 
recorded before dosing. The same equipment should be used throughout the study, if possible. To 
obtain the actual body weight, patients must be weighed lightly clothed. 
Physical examinations will be performed at each study site visit. At dosing visits, physical 
examinations will be performed before dosing. A physical examination includes, per the 
institutional guidelines, the evaluation of general appearance, skin, head, eyes, ears, nose, mouth, 
oropharynx, neck, heart, lungs, abdomen (including liver and spleen), extremities, lymph nodes, 
neurological and musculoskeletal systems, and genitourinary system/pelvis (at the Investigator¶s 
discretion). 
If the Investigator (or qualified designee) encounters an abnormal finding, the Investigator should 
indicate whether the finding is clinically significant or not. Information about the physical 
examination must be present in the source documentation at the study site. Significant findings, 
except for SAEs, that are present prior to signing the ICF must be included on the Medical History 
eCRF. Significant findings that meet the definition of an AE, must be recorded on the AE eCRF.  
8.11 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status assessment should be performed at each study site visit. At dosing 
visits, ECOG performance status will be assessed before dosing. See Appendix C for details of 
ECOG performance status scoring.  
8.12 
Pregnancy Test 
Female patients of childbearing potential must have a negative serum pregnancy test at screening 
and before dosing (within 72 hours) at Visit 1 of Cycle 1, and a urine pregnancy test should be 
performed at all other visits indicated in Appendix A. 
In this study, pregnancies occurring during participation (including pregnancies of partners of 
male patients) will not be considered as AEs or SAEs but must be reported to the Sponsor using 
the study Pregnancy Reporting Form. See Section 8.4 for details regarding pregnancy reporting.  

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8.13 
Thyroid Function Testing 
In clinical studies using pembrolizumab, thyroid function needs to be evaluated at regular time 
intervals. Blood samples for thyroid function testing will be performed locally at screening and 
Visit 1 of each cycle from Cycle 2 onward.  
The thyroid panel should include triiodothyronine or free triiodothyronine, free thyroxine, and 
thyroid-stimulating hormone. 

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9 
STATISTICS 
9.1 
Analysis Sets 
The Full Analysis Set (FAS) will include all patients who receive an injection of CyPep-1. The 
FAS will be used in the analysis of efficacy and exploratory endpoints. 
The Evaluable Analysis Set (EAS) will include all patients who receive an injection of CyPep-1 
on at least 2 treatment days, receive at least 1 administration of pembrolizumab, and have at least 
1 post-baseline tumor response assessment after the first injection of CyPep-1 (Cycle 1 Visit 1).  
The Safety Analysis Set (SAS) will include all patients who receive at least 1 injection of CyPep-1 
or at least 1 administration of pembrolizumab. The SAS will be the basis of safety analyses.  
9.2 
Statistical Methods 
9.2.1 
Analysis of Efficacy 
Analysis of efficacy will be conducted in Phase 2a. Efficacy analyses will be done using the FAS. 
The Objective Response Rate (ORR) will be based on the number of patients achieving a partial 
response (PR) or CR based on RECIST v1.1 and iRECIST (Appendix D). Best overall response 
will also be calculated. The Disease Control Rate will be based on the number of patients achieving 
a PR, CR, or stable disease 16 weeks based on RECIST v1.1 and iRECIST (Appendix D). 
Progression Free Survival (PFS) (percentage of patients alive and progression-free) at 6, 12, 18, 
and 24 months after the first treatment with CyPep-1 + pembrolizumab will be determined. A 
progression event is defined as disease relapse or progression (based on all lesions) or death due 
to any cause. For patients who are not known to have died or progressed as of the data cut-off date, 
PFS will be censored at the date of the last objective progression-free disease assessment. Patients 
who discontinue the study treatment without post-treatment assessments will be treated as 
non-responders. The detailed censoring rules will be specified in the Statistical Analysis Plan. 
Sensitivity analysis for primary efficacy endpoints will be provided using the EAS. An exploratory 
analysis of itRECIST will be applied to allow for a separate response assessment of injected and 
non-injected lesions. 
9.2.2 
Analysis of Safety 
Safety analysis will be conducted in both Phase 1b and Phase 2a using the SAS. TEAE incidence 
rates will be described by the frequency of TEAEs and categorized by preferred term and system 
organ class according to the NCI CTCAE v5.0. TEAEs will be summarized by seriousness, grade, 
and relationship to CyPep-1 and pembrolizumab. The incidence of TEAEs will be evaluated for 
each study arm and for all patients combined. The following data will be summarized using 
descriptive statistics: treatment exposure, disposition, vital signs, body weight, 12-lead ECG 
parameters, and laboratory assessments. Shift tables showing changes from baseline will be 
generated where appropriate. Summaries will be by arm and for all patients. 
The incidence of DLT events during the DLT period will be presented. 

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9.2.3
Analysis of Pharmacokinetics 
Phase 1b patients who have received CyPep-1 and have provided 1 evaluable pre-dose and at least 
1 post-dose PK blood sample will be evaluable for PK. Standard methodology will be used to 
estimate PK parameters. Concentration-time profiles will be derived for patients with post-dose 
samples. 
9.2.4
Sample Size Determination 
The Simon¶s 2-Stage Design is used in the Phase 2 portion, which allows the study to be stopped 
for futility and provides a recommendation for continuation from Stage 1 to Stage 2. 
CATALYST is a hypothesis-generating study for the combination of CyPep-1 with 
pembrolizumab. The hypothesis implemented in the Simon¶s 2-Stage Design disease model uses 
the historical objective responses observed in pembrolizumab single-agent Phase 2 trials. The 
rationale and statistical details are provided in the key references of the 3+3 dose-escalation design 
for Phase 1 trials in oncology. 
The sample size for the Phase 1b portion of the study is based on practical determinations. The 
first 6 patients of the study are planned to be enrolled in the Phase 1b portion. Approximately 
90 patients will be enrolled, with 30 patients per arm. Assuming 10% of enrolled patients will not 
have evaluable post-baseline tumor response data, it is expected that approximately 27 patients 
will be included in the evaluable set in each arm. 
While all endpoints will be reviewed to assess activity of CyPep-1, and the sample size is based 
on practical rather than statistical considerations, the level of precision that is achieved for 
27 patients on the primary endpoint, ORR, is as follows: 
A sample size of 27 patients will produce a 2-sided exact 80% confidence interval of 34.4% to 
62.0% when the sample proportion is 48% (13/27) and an interval of 38.1% to 65.5% when the 
sample proportion is 52% (14/27). The lower bounds are computed through an exact binomial test.  
The Simon¶s 2-Stage Design will be used in the Phase 2 portion to determine whether CyPep-1 
has sufficient anti-tumor activity to warrant further development for patients with advanced or 
metastatic HNSCC, melanoma, or TNBC. A true ORR 9% is considered insufficient to warrant 
further study (null hypothesis), whereas a true ORR 25% is considered sufficiently effective 
(alternative hypothesis). The number of patients in each stage and the minimum number of patients 
achieving objective response (CR + PR) per RECIST v1.1 needed to continue to the next stage 
will be determined based on the Simon¶s 2-Stage Design with 80% power and a 1-sided 
significance level of 10% for each arm separately. Based on this design, up to 16 evaluable patients 
will be accrued for Stage 1. If 1 patient of these 16 patients achieves objective response 
(CR + PR) per RECIST v1.1, the enrollment for the expansion cohort will terminate. Otherwise, 
10 additional evaluable patients will be evaluated in Stage 2. In order to enroll the required number 
of evaluable patients, it is anticipated that approximately 18 and 12 patients (total of approximately 
30 patients) will be enrolled into Stages 1 and 2, respectively. Upon completion of Stage 2, if 
>4 patients out of the total 26 evaluable patients achieve objective response (CR + PR) per 
RECIST v1.1, then the null hypothesis will be rejected. If the required minimum number of 
responses is observed prior to completion of enrollment, then the transition between the first and 
second stages will occur without interruption. If the minimum is not observed at the time 
Sample Size Determination 
The Simon¶s 2-Stage Design is used in the Phase 2 portion, which a
d
llows the study to be stopped 
g
g
p
,
y
for futility and provides a recommendation for continuation from Stage 1 to Stage 2. 
CATALYST is a hypothesis-generating study for the combination of CyPep-1 with
yp
g
g
y
y
p
pembrolizumab. The hypothesis implemented in the Simon¶s 2-Stage Design disease model uses 
p
yp
p
g
g
the historical objective responses observed in pembrolizumab single-agent Phase 2 trials. The
j
p
p
g
g
rationale and statistical details are provided in the key references of the 3+3 dose-escalation design 
for Phase 1 trials in oncology. 
The sample size for the Phase 1b portion of the study is based on practical determinations. The 
p
p
y
p
first 6 patients of the study are planned to be enrolled in the Phase 1b portion. Approximately 
p
y
p
p
pp
y
90 patients will be enrolled, with 30 patients per arm. Assuming 10% of enrolled patients will not 
p
,
p
p
g
p
have evaluable post-baseline tumor response data, it is expected that approximately 27 patients 
p
p
will be included in the evaluable set in each arm. 
While all endpoints will be reviewed to assess activity of CyPep-1, and the sample size is based 
p
y
y
p
,
p
on practical rather than statistical considerations, the level of precision that is achieved for 
p
,
27 patients on the primary endpoint, ORR, is as follows: 
A sample size of 27 patients will produce a 2-sided exact 80% confidence interval of 34.4% to 
p
p
p
62.0% when the sample proportion is 48% (13/27) and an interval of 38.1% to 65.5% when the 
p
p
p
(
)
sample proportion is 52% (14/27). The lower bounds are computed through an exact binomial test. 
The Simon¶s 2-Stage Design will be used in the Phase 2 portion to determine whether CyPep-1 
g
g
p
y
p
has sufficient anti-tumor activity to warrant further development for patients with advanced or 
y
metastatic HNSCC, melanoma, or TNBC. A true ORR 
p
p
9% is considered insufficient to warrant 
further study (null hypothesis), whereas a true ORR 25% is considered sufficiently effective 
y (
yp
),
y
(alternative hypothesis). The number of patients in each stage and the minimum number of patients
(
yp
)
p
g
p
achieving objective response (CR + PR) per RECIST v1.1 needed to continue to the next stage 
g
j
p
(
) p
g
will be determined based on the Simon¶s 2-Stage Design with 80% power and a 1-sided 
g
g
p
significance level of 10% for each arm separately. Based on this design, up to 16 evaluable patients 
g
will be accrued for Stage 1. If 
p
y
g
p
p
1 patient of these 16 patients achieves objective response 
g
p
p
j
p
(CR + PR) per RECIST v1.1, the enrollment for the expansion cohort will terminate. Otherwise, 
(
) p
,
p
,
10 additional evaluable patients will be evaluated in Stage 2. In order to enroll the required number 
p
g
q
of evaluable patients, it is anticipated that approximately 18 and 12 patients (total of approximately 
p
,
p
pp
y
p
(
pp
y
30 patients) will be enrolled into Stages 1 and 2, respectively. Upon completion of Stage 2, if
p
)
g
,
p
y
p
p
g
,
>4 patients out of the total 26 evaluable patients achieve objective response (CR + PR) per 
p
p
j
p
(
) p
RECIST v1.1, then the null hypothesis will be rejected. If the required minimum number of
,
yp
j
q
responses is observed prior to completion of enrollment, then the transition between the first and 
n
p
p
p
,
second stages will occur without interruption. If the minimum 
t
is not observed at the time 

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enrollment is completed, then enrollment in the second stage will be held until the continuation 
criterion is met. 
enrollment is completed, then enrollment in the second stage will be held until the continuation 
criterion is met. 

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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the study 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. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All study 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 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
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. 
10.1.5 
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 study site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
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 study site. Source data are 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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10.3 
End of Study 
The end of the study (³study completion´) is defined as the date of the last protocol-specified 
visit/assessment for the last patient in the study.  

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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
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 subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being 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. 
11.2 
Institutional Review Board/Independent Ethics Committee 
The IRB/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 study sites where IRB/IEC 
approval has been obtained. The protocol, IB, 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 must 
be approved by the IRB/IEC. 
No study drug will be released to the study site for dosing until written IRB/IEC authorization has 
been received by the Sponsor. 
For European study sites, it is the responsibility of the Sponsor or their designee (ie, Medpace) to 
obtain the approval of the responsible ethics committees according to the national regulations.  
The study will only start in the respective study sites once the respective committee¶s written 
approval has been given. 
11.3 
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. 

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11.4 
Subject Card  
On enrollment in the study, the patient will receive a subject card to be carried at all times. The 
subject card will state that the patient is participating in a clinical research study, type of treatment, 
and contact details in case of an SAE. 
11.5 
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 study site personnel the following documents: protocol, IB, eCRFs and 
procedures for their completion, informed consent process, and the procedure for reporting SAEs. 
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 study 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 study site by signature and date on the study-specific monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, competent authority, 
the Sponsor or their designee, applicable foreign health authorities, and the IRB/IEC as 
appropriate. Patients 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. 
11.7 
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. 

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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. 
11.8 
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. 
11.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. Details of the financial aspects of the study are 
addressed in the Clinical Study Agreement. 
11.10 
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. 
11.11 
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.  
11.12 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this study will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the study. 

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
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 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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13 
REFERENCES 
 
 
1. 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567.  
2. 
Kitano S, Nakayama T, Yamashita M. Biomarkers for immune checkpoint inhibitors in 
melanoma. Front Oncol. 2018;8:270.  
3. 
Oliva M, Spreafico A, Taberna M, et al. Immune biomarkers of response to 
immune-checkpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol. 
2019;30(1):57±67. 
4. 
Prelaj A, Tay R, Ferrara R, et al. Predictive biomarkers of response for immune checkpoint 
inhibitors in non±small-cell lung cancer. Eur J Cancer. 2019;106:144-159. 
5. 
Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint 
blockade-based combination therapies. Cancer Cell. 2018;33(4):581-598.  
6. 
Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65(3):1089-1096.  
7. 
Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 
2004;64(3):1140-1145.  
8. 
Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37(5):430-439.  
9. 
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-6505.  
10. 
Spranger S, Koblish HK, Horton B, et al. Mechanism of tumor rejection with doublets of 
CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and 
proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother 
Cancer. 2014;2:3.  
11. 
Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280.  
12. 
Pilon-Thomas S, Mackay A, Vohra N, et al. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. 
J Immunol. 2010;184(7):3442-3449.  
13. 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. 
Clin Cancer Res. 2007;13(7):2151-2157.  
14. 
Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory 
receptor programmed death-1. Immunity. 2004;20(3):337-347. 
15. 
Investigator¶s Brochure for CyPep-1. Version 3.0, 30 September 2020.  
16. 
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. N Engl J Med. 2014;371(23):2189-2199.  
17. 
Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 
2015;348(6230):69-74.  
18. 
Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after 
immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206.  
 

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19. 
Vesely MD, Schreiber RD. Cancer immunoediting: antigens, mechanisms, and 
implications to cancer immunotherapy. Ann N Y Acad Sci. 2013;1284(1):1±5.  
20. 
Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based 
immunotherapy. Lancet Oncol. 2016;17(12):e542±e551.  
21. 
Huerter MM, Ganti AK. Predictive biomarkers for immune checkpoint inhibitor therapy: 
we need to keep searching. J Thorac Dis. 2018;10(Suppl 18):S2195±S2197.  
22. 
Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell 
infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-1119.e10.  
23. 
Investigator¶s Brochure for MK-3475 (pembrolizumab). Edition 21, 02 September 2021. 
24. 
Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and Progesterone Receptor 
Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol. 2020;38(12):1346-
1366. 
25. 
Ternyila D. FDA approves every-6-week pembrolizumab dosage. Targeted Oncology. 
https://www.targetedonc.com/view/fda-approves-every-6-week-pembrolizumab-dosage. 
Accessed 16 December 2021.  
26. 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. European medicines agency adopts 
positive opinion for Merck¶s KEYTRUDA® (pembrolizumab) for six-week dosing 
schedule across all current monotherapy indications. 
https://www.merck.com/news/european-medicines-agency-adopts-positive-opinion-for-
mercks-keytruda-pembrolizumab-for-six-week-dosing-schedule-across-all-current-
monotherapy-indications/. Accessed 16 December 2021. 
27. 
Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in 
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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen/urea 
C-reactive protein 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
 
Hematology 
Absolute neutrophil count 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
1. 
Including neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Manual microscopic review is performed 
only if white blood cell count and/or differential values are out of reference range. 
 
Coagulation 
Activated partial thromboplastin time 
International normalized ratio [1] 
Prothrombin time 
 
1. 
In case there are no normal ranges available for the prothrombin time, the international normalized ratio may be used 
instead of prothrombin time. 
 
Urinalysis 
Bilirubin 
Blood [1] 
Creatinine 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [2] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
1. 
Including hemoglobin and erythrocytes.  
2. 
Microscopy is performed only as needed based on positive dipstick test results. 
 
Pregnancy Test [1] 
Serum human chorionic gonadotropin 
Urine human chorionic gonadotropin 
1. 
For female patients of childbearing potential only. 

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Endocrinology 
Follicle-stimulating hormone [1] 
Free thyroxine 
Thyroid-stimulating hormone 
Triiodothyronine [2] 
1. 
Follicle-stimulating hormone will only be performed in female patients who have spontaneous amenorrhea for at least 
2 years to verify their post-menopausal status. 
2. 
Or free triiodothyronine. 
 
Serology 
Human immunodeficiency virus 
 
 

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APPENDIX C:  EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS SCORING 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 

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APPENDIX D:  DESCRIPTION OF THE iRECIST PROCESS FOR 
ASSESSMENT OF DISEASE PROGRESSION 
Immune-Response Evaluation Criteria in Solid Tumors (iRECIST) is based on the Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 but adapted to account for the unique 
tumor response seen with immunotherapeutic drugs. iRECIST will be used by the Investigator to 
assess tumor response and progression and to guide decisions about changes in management. 
Assessment at Screening and Prior to the RECIST v1.1 Progression 
Until radiographic disease progression based on modified RECIST v1.1, there is no distinct 
iRECIST assessment. 
Assessment and Decision at the RECIST v1.1 Progression 
For patients who show radiological progressive disease (PD) by RECIST v1.1, the Investigator 
will decide whether to continue a patient on study treatment until repeat scans are obtained.  
Tumor flare may manifest as any factor causing radiographic progression per RECIST v1.1, 
including: 
 Increase in the sum of diameters of target lesion(s) identified at baseline to 20% and 5 mm 
from nadir; 
Note: The iRECIST publication uses the terminology ³sum of measurements,´ but ³sum of 
diameters´ will be used in this protocol, consistent with the original RECIST v1.1 terminology. 
 Unequivocal progression of non-target lesion(s) identified at baseline; and 
 Development of new lesion(s). 
iRECIST defines new response categories, including unconfirmed PD (iUPD) and confirmed 
progressive disease (iCPD). For purposes of iRECIST assessment, the first visit showing 
progression according to RECIST v1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression.  
At this visit, target and non-target lesions identified at baseline by RECIST v1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST v1.1. From measurable new lesions, up to 
5 lesions total (up to 2 per organ), may be selected as New Lesions ± Target. The sum of diameters 
of these lesions will be calculated and kept distinct from the sum of diameters for target lesions at 
baseline. All other new lesions will be followed qualitatively as New Lesions ± Non-target. 
Assessment at the Confirmatory Scans 
On the confirmatory scans, the patient will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of 
iUPD), or as showing disease stability or response (stable disease [iSD]/partial 
response [iPR]/complete response [iCR]). 

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Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 Any of the factors that were the basis for the initial iUPD show worsening; or 
o For target lesions, worsening is a further increase in the sum of diameters of 5 mm, 
compared to any prior iUPD time point; 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to 
a prior iUPD time point; this does not have to meet the ³unequivocal´ standard of 
RECIST v1.1; or 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by 5 mm from a prior iUPD time 
point;  
 Visible growth of new non-target lesions; or 
 The appearance of additional new lesions. 
 Any new factor appears that would have triggered PD by RECIST v1.1. 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 None of the progression-confirming factors identified above occurs; AND 
 The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST v1.1). 
Additional scans for confirmation are to be scheduled 4 weeks to 8 weeks from the scans on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan will proceed in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 None of the progression-confirming factors identified above occurs; AND 
 The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudoprogression, and the level of suspicion for 
progression is ³reset.´ This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 

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Management Following the Confirmatory Scan 
If repeat scans do not confirm PD per iRECIST, as assessed by the Investigator, study intervention 
is to continue, and the regular scan schedule is to be followed. If PD is confirmed, patients may be 
discontinued from study intervention. 
Note: If a patient has confirmed radiographic progression (iCPD), clinically meaningful study 
intervention may be continued after consultation with the Sponsor. In this case, if study treatment 
is continued, tumor imaging should continue to be performed following the intervals as outlined 
in Section 7.2. 
Detection of Progression at Visits After Pseudoprogression Resolves 
After resolution of pseudoprogression (ie, after iSD/iPR/iCR), another instance of progression 
(another iUPD) is indicated by any of the following events: 
 Target lesions; 
o Sum of diameters reaches the PD threshold ( 20% and 5 mm increase from nadir) either 
for the first time, or after resolution of previous pseudoprogression. The nadir is always the 
smallest sum of diameters seen during the entire study, either before or after an instance of 
pseudoprogression. 
 Non-target lesions; or 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first-time results in iUPD; or  
o If non-target lesions have shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target lesions, 
taken as a whole. 
 New lesions; 
o New lesions appear for the first time; 
o Additional new lesions appear; 
o Previously identified new target lesions show an increase of 5 mm in the new lesion sum 
of diameters, from the nadir value of that sum; or 
o Previously identified non-target lesions show any significant growth. 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Scans above) is repeated. Progression 
must be confirmed before iCPD can occur. 
The decision process on the subsequent iUPD is identical to the iUPD confirmation process for 
the initial PD, with 1 exception, which could occur if new lesions had occurred at a prior instance 
of iUPD, had not resolved, then worsened (increase in size or number) leading to the second iUPD. 
If new lesion worsening has not resolved at the confirmatory scan, then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution 
to iSD or iPR, or until new or worsening causes of progression indicates iCPD. 

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Additional details about the iRECIST are provided in the iRECIST publication.1  
 
1 Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 

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APPENDIX E:  itRECIST GUIDANCE 
Intratumoral-Response Evaluation Criteria in Solid Tumors (itRECIST) is based on the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-RECIST but adapted to 
account for the unique tumor response seen with intra-tumoral immunotherapeutic drugs. 
itRECIST will be used by the Investigator to assess tumor response.1 
 
1 Goldmacher GV, Khilnani AD, Andtbacka RHI, et al. Response Criteria for Intratumoral Immunotherapy in Solid 
Tumors: itRECIST. J Clin Oncol. 2020;38(23):2667-2676.