CyPep-1 Injections in Cancer Inducing Lymphocyte Infiltrate Accumulations

Exclusion Criteria

• •For Phase I and Phase IIa Arms A, C, and D: subjects who meet any of the following criteria at screening will be excluded from trial entry:
• •1. There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds delivered by IT injection to the to-be injected lesion(s), including investigational agents. Subjects with prior IT therapies are allowed in Arm D.
• •2. Participation in another clinical trial within 4 weeks prior to first dose of CyPep-1.
• •3. Anti-cancer therapy within 4 weeks prior to the first dose of CyPep-1 (within 2 weeks for palliative radiotherapy, within 1 week for endocrine therapy).
• •4. Major surgical procedure within 14 days prior to the first dose of CyPep-1.
• •5. Live vaccine within 30 days prior to first dose of CyPep-1.
• •6. Expected to require any other form of systemic or localized antineoplastic therapy while in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor lesions that are not selected for evaluation of treatment response.
• •7. Clinical evidence of an active second malignancy that is progressing or requires active treatment, except for curatively treated early stage (carcinoma in situ or stage 1) carcinomas or non-melanoma skin cancer.
• •8. Active autoimmune disease requiring immunosuppressive therapy.
• •9. Any condition requiring continuous systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive agents within 2 weeks prior to 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 auto-immune disease.
• •10. Abnormal or clinically significant coagulation parameters:
• •1. Prothrombin Time - International Normalized Ratio (PT-INR) ≥ 1.5 ULN
• •2. Activated Partial Thromboplastin Time (APTT) ≥ 1.5 ULN Subjects being treated with anticoagulants are excluded if the coagulation parameters are outside the therapeutic intervals as described in the Summary of Product Characteristics (SmPC) for the administered treatment.
• •11. Subjects on anticoagulants with temporarily stop and start, supported by low molecular weight heparin (or other anticoagulation therapy at the discretion of the investigator and/or per local standard of care) during treatment period.
• •12. Known hypersensitivity to any component of CyPep-1.
• •13. Prior allogeneic tissue/solid organ transplant, stem cell or bone marrow transplant.
• •14. Known active human immunodeficiency virus (HIV). Subject is eligible when normal levels of Cluster of Differentiation 4 (CD4) are present.
• •15. Central nervous system (CNS) metastasis that is symptomatic or progressing or that requires current therapy (e.g., evidence of new or enlarging CNS metastasis, carcinomatous meningitis or new neurological symptoms attributable to CNS metastasis).
• •16. QTcF (QT corrected for heart rate by Fridericia's cube root formula)\> 480 ms, history of long or short QT syndrome, Brugada syndrome, or known history of QTc (Corrected QT Interval) prolongation, or Torsade de Pointes.
• •17. Women who are pregnant or breastfeeding.
• •18. Any serious and/or unstable pre-existing medical, psychiatric or other condition which in the investigator's opinion could interfere with subject safety, obtaining written informed consent, or compliance with the trial protocol.
• •19. Subject is a candidate for hepatic surgery or local regional therapy of liver metastases with curative intent.
• •20. More than one third of the liver is estimated to be involved with metastases.
• •21. There is invasion by cancer into the main blood vessels such as the portal vein, hepatic vein or the vena cava.
• •22. Subject is currently receiving or has received liver metastatic-directed therapy (eg: radiation, ablation, embolization) less than 4 weeks prior to enrolment or hepatic surgery.
• •Participants are excluded from the trial if ANY of the following criteria apply at screening:
• •23. A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to trial treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• •24. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., Cytotoxic T-lymphocyte-associated protein (CTLA) 4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE).
• •25. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (within 1 week for endocrine therapy) prior to first dose of CyPep-1.
• •26. Has received prior (palliative) radiotherapy within 2 weeks of start of trial treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• •27. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of CyPep-1. Note: Administration of killed vaccines are allowed.
• •28. Has received prior compounds delivered by IT injection to the to-be injected lesion(s), including investigational agents.
• •29. Expected to require any other form of systemic or localized antineoplastic therapy while in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor lesions that are not selected for evaluation of treatment response.
• •30. Ongoing pembrolizumab-related toxicity event(s) as per Treatment Limiting Toxicity (TLT) definition.
• •31. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
• •32. Has had an allogeneic tissue/solid organ transplant.
• •33. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of CyPep-1.
• •34. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years, except for curatively treated early stage (carcinoma in situ or stage 1) carcinomas or non-melanoma skin cancer.
• •Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• •35. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• •36. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or to another mAb, as well as any known hypersensitivity to any component of CyPep-1.
• •37. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• •38. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
• •39. Has an active infection requiring systemic therapy.
• •40. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
• •41. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as Hepatitis C virus (HCV) RNA \[qualitative\] is detected) infection.
• •42. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• •43. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
• •44. Has received radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of trial treatment (applicable only for subjects with non-small cell lung cancer \[NSCLC\], mesothelioma and small cell lung cancer \[SCLC\]).