A Study to Evaluate the Safety and Efficacy of CyPep-1 in Combination With Pembrolizumab for the Treatment of Advanced or Metastatic Cancers

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.

Treatment with immune modulating agents may result in long lasting anti-tumor responses in patients with cancer. However, only a subset of patients obtains durable remission. Treatment strategies that aim at recruiting tumor antagonizing cellular components of the immune system holds great promise.

CyPep-1 is a chemically synthesized peptide with oncolytic properties. It selectively targets cancer cells based on their altered molecular composition, and removes the surrounding cell membrane. This releases tumor neoantigens to the microenvironment and potentially induces an anti-tumour immune response.

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.

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).

Eligibility Criteria:
Inclusion Criteria:

General Inclusion Criteria

1. Is 18 years of age or older on the day of signing informed consent;
2. Provides written informed consent and is able to comply with study procedures and assessments;
3. Has measurable disease as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1;
4. Has at least 1 non-ulcerated, measurable, and accessible lesion for intra-tumoral (IT) injection with a maximum diameter of 5 cm;
5. Is able to provide tissue from a core or excisional biopsy at screening or has an acceptable stored tumor sample available that was collected within 90 days prior to screening;
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
7. Has 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 CyPep-1.
10. If a male patient is able to father children, he must agree to use 2 acceptable methods of contraception throughout the study (eg, condom plus permicidal gel). Sperm donation is not recommended from the time of signing the ICF until at least 120 days after the last administration of CyPep-1
11. Has adequate organ function. 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 failed or progressed on or after prior platinum-based therapy OR has failed or progressed on or after treatment with a checkpoint inhibitor administered either as monotherapy or in combination with other therapies (if immune checkpoint inhibitor \[ICI\] eligible based on programmed cell death ligand 1 \[PD-L1\] status).

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;
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).

Exclusion Criteria:

1. Has only non-palpable cutaneous infiltrations (eg, breast cancer cutaneous carcinomatosis);
2. Had anti-cancer therapy within 4 weeks prior to the first dose of CyPep-1 (2 weeks for palliative radiotherapy);
3. Has participated in a clinical trial and received an investigational therapy within 30 days prior to the first dose of CyPep-1;
4. Has received or will receive a live or live attenuated vaccine within 30 days prior to the first dose of CyPep-1; 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 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.
5. Has 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. Has had a major surgical procedure within 14 days prior to the first dose of CyPep-1;
7. Is expected to require a systemic or localized antineoplastic 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. Is pregnant or breastfeeding;
9. Has 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. Has 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 CyPep-1; 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. Has 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 CyPep-1. 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. Has 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 anticoagulants in which case it must be within appropriate clinical levels; Note: Patients who are on anticoagulants 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. Has 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. Has a known hypersensitivity to any component of CyPep-1 or pembrolizumab;
15. Has 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. Has an active infection requiring systemic therapy;
17. Has a known history of Hepatitis B or known active Hepatitis C virus infection;
18. Has had radiotherapy within 2 weeks prior to the first dose of CyPep-1, is in recovery from radiation toxicity, or has had radiation pneumonitis;
19. Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease;
20. Has had a prior allogeneic tissue/solid organ transplant, stem cell, or bone marrow transplant;
21. Has active human immunodeficiency virus (HIV). Patient is eligible when on stable antiretroviral therapy (no change in medication or dose) for at least 4 weeks prior to screening, has 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 has 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. Has a central nervous system (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. Has 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: persons deprived of liberty by a judicial or administrative decision; adult persons subject to a legal protection measure (under supervision/under guardianship); or persons under a judicial protection measure; or
26. Has 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.