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)

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;
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.

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;
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.
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 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.