Advanced Solid Tumor Malignancy
Conditions
Keywords
Cancer, Tumour, Oncology, Immunotherapy, Oncolytic, Cluster of Differentiation 8 (CD8)), Intratumoral, Neoplasm
Brief summary
This Phase I/IIa trial is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of CyPep-1 when administered directly into malignant tumors in monotherapy and in combination with anti programmed cell death protein 1(anti-PD-1) antibody pembrolizumab. Additionally, the trial will monitor anti-tumor effects on both injected lesions and distant non-injected deposits.
Detailed description
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 showing that CyPep-1 can synergize with anti-PD-1 antibody treatment in terms of decreased tumor volumes and prolonged survival highlight the possible clinical utility of CyPep-1 in the combination setting with Immune checkpoint inhibitors (ICIs). This is a phase I/IIa, open label trial, with a dose escalation phase to evaluate the safety and tolerability of CyPep-1 as monotherapy and in combination with pembrolizumab, to identify the recommended phase 2 dose, followed by a dose expansion phase in subjects with advanced solid tumors. The trial consists of two phases and multiple arms. Secondary objectives are preliminary anti-tumor efficacy and to assess the pharmacokinetics (PK) of CyPep-1 as monotherapy and in combination with pembrolizumab. As part of the exploratory analysis, it is planned to determine local and systemic immunological effects after CyPep-1 administration, alone and in combination with pembrolizumab.
Interventions
DRUGCyPep-1
Intratumoral injection
IV infusion
Sponsors
Cytovation AS
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For Phase I and Phase IIa Arms A and C: 1. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic tumors (solid tumor or lymphoma) with an accessible tumor lesion for intratumoral injection of CyPep-1 malignancy (including lymphomas) that is either: 1. Refractory to standard-of-care treatment 2. Have a disease for which there is no standard therapy considered appropriate. Metastatic deposits (including cutaneous/subcutaneous lesions and metastatic deposits in lymph nodes) of tumors for which IT injections may be performed are eligible. Pure cutaneous infiltrations (e.g., breast cancer cutaneous carcinomatosis) are ineligible. 2. 1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and measurable as defined by Immune Response Evaluation Criteria in Solid Tumors (iRECIST). All other tumor lesion(s) may be selected for efficacy follow-up but will not be subjected to treatment with CyPep-1. 3. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy at screening and at Week 6. For Arm C: 4. Confirmation of the presence of at least 1 liver metastasis by imaging. 5. Subjects must have measurable disease which is equal to one or more metastatic liver lesions that can be accurately and serially measured that are greater than 1 cm dimension and for which the longest diameter is greater or equal to 1 cm as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). The metastatic liver lesion must not be in an area that received prior localized therapies. 6. Metastatic liver lesion for injection with \>50% radiological visible necrosis must be avoided and the lesion must be located where any tumor swelling will not lead to gall bladder tract obstruction or lead to bleeding risk. For Arm D: 7. Histologically or cytologically confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV: M1a) melanoma considered incurable by Standard of Care. For metastatic melanoma, only distal cutaneous, subcutaneous, or lymph node metastases are allowed. 8. Previously exposed to ICI(s) and be categorized following the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce meeting one of the following: a. Have primary resistance: PD-(L)-1 inhibitor exposure ≥6 weeks and have the best response as one of the following: i. Progressive disease/ Disease progression (PD), ii. Stable Disease (SD) for \<6 months. b. Have secondary resistance: PD-(L)-1 inhibitor exposure ≥6 weeks and best response Complete response (CR), Partial Response (PR), or SD \>6 months. c. Have adjuvant therapy resistance: recurrence subcategorized into primary resistance/early relapse occurred \<12 weeks after the last dose, and late relapse occurred ≥12 weeks after the last dose. If B-Raf gene (BRAF) mutated, patients must have progressed to treatment with BRAF inhibitors. d. Have neoadjuvant therapy resistance including subjects with or without major pathologic response and subsequent PD that fulfills criteria for primary or secondary resistance e. Discontinued from ICI(s) therapy due to immune-related adverse events grade 3 or 4 other than endocrine insufficiencies treatable with hormonal replacement therapy, and meet one of the following: i. Remain on SD at discontinuation of PD-(L)1 inhibitor in combination with ipilimumab or show regrowth after \<12 weeks of the last dose ii. Have not achieved a CR with single-agent PD-(L)1 inhibitor or combination of PD-(L)1 with Lymphocyte activation gene-3 (LAG-3) inhibitor 9. At least 1 non-ulcerated lesion, not exceeding 5 cm in (the longest) diameter, for intratumoral injection(s) and measurable as defined by iRECIST. 10. Resolution of toxicity due to prior therapy returned to baseline or \< Grade 2, except for alopecia or other irreversible immune-mediated AEs, as defined by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. and SITC ICI-related Adverse events (AEs). 11. Prior treatment(s) delivered by IT injection to the to-be injected lesion(s), including investigational agents, is allowed. For Phase I and Phase IIa Arms A, C, and D in addition: 12. Age ≥ 18 years. 13. Estimated life expectancy of at least 3 months. 14. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 15. Resolution of toxicity due to prior therapy to Grade \< 2 (except for alopecia and transaminases in case of liver metastases) as defined by CTCAE v5.0. 16. Ability to give written informed consent and to comply with the protocol. 17. All subjects of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must have a negative highly sensitive pregnancy test at screening (urine/serum) and agree to use highly effective method for contraception according to the European Union (EU) Clinical Trial Facilitation Group guidance from time of signing the informed consent form (ICF) until at least 120 days after the last administration of CyPep-1. The partners of subjects with childbearing potential must also apply contraceptive methods and are recommended not to donate sperm. 18. Adequate bone marrow, liver, and renal function: 1. Platelet count ≥ 100 x 109/L 2. Hemoglobin ≥ 6.0 mmol/L or 9.67 g/dL 3. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L 4. Total bilirubin ≤ 1.5 x Upper limit of normal (ULN), except for subjects with familial bilirubinemia (Gilbert's disease) 5. Serum Aspartate transaminase (ASAT) and Alanine transaminase (ALAT) ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases) 6. Creatinine clearance ≥ 30 mL/min (by CKD-EPI formula). For Phase IIa Arm B: Participants are eligible to be included in Arm B of the trial only if all of the following criteria apply: 19. The participant provides written informed consent for the trial. 20. Be ≥ 18 years of age on day of signing informed consent. 21. Participant with histologically or cytologically confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) solid tumor malignancy (including lymphomas) that is refractory to standard-of-care treatment or for which there is no standard therapy considered appropriate. Metastatic deposits (including cutaneous/subcutaneous lesions and metastatic deposits in lymph nodes) of tumors for which IT injections may be performed are eligible. Pure cutaneous infiltrations (e.g., breast cancer cutaneous carcinomatosis) are ineligible. 22. Subjects must have progressed on treatment with an anti-Programmed cell death protein 1 (PD1)/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. Treatment progression is defined by meeting all of the following criteria: 1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 2. Has demonstrated clinical or radiological disease progression (PD) after PD-1/L1 23. A male participant must agree to use contraception and refrain from sperm donation during the treatment period and for at least 120 days after the last dose of trial medication. 24. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) 2. A WOCBP (defined as \< 2 years after last menstruation or not surgically sterile) must have a negative highly sensitive pregnancy test at screening (urine/serum) and must follow contraceptive guidance (highly effective method for contraception according to the EU Clinical Trial Facilitation Group guidance) from time of signing the ICF until at least 120 days after the last administration of trial medication. The partners of subjects with childbearing potential must also apply contraceptive methods and are recommended not to donate sperm. 25. 1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and measurable as defined by iRECIST. All other tumor lesion(s) may be selected for efficacy follow-up but will not be subjected to treatment with CyPep-1. 26. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy at screening and at Week 6. 27. Have an ECOG performance status of 0 to 1. 28. Have adequate organ function as defined in the following table. Specimens must be collected within 10 days (or less) prior to the start of trial treatment. 29. Only for subjects with lymphoma: have measurable disease defined as at least one lesion that can be accurately measured in at least two dimensions with spiral CT scan. Minimum measurement must be \> 15 mm in the longest diameter by \> 10 mm in the short axis. 30. Estimated life expectancy of at least 3 months. 31. Human immunodeficiency virus (HIV) infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease.
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. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Type and Number of Adverse Events (AEs) | From Informed Consent Form (ICF) signing until Follow Up (FU) or until End of Treatment (EoT) visit. After FU visit, only ongoing AEs or Serious Adverse Events (SAEs) related to CyPep-1 were collected. Duration: up to a maximum of 28 months. | According to National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) criteria v5.0, and additional safety parameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to approximately 28 months | 28 days after the date of the initial response, defined by complete response (disappearance of all target lesions) and partial responses (\>=30% decrease in the sum of the longest diameter of target lesions), according to Immune Response Evaluation Criteria in Solid Tumors (iRECIST). |
Countries
France, Netherlands, Spain
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 11.2 |
| ECOG Grade 0 | 1 Participants |
| ECOG Grade 1 | 1 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 4 / 5 | 6 / 6 | 13 / 18 | 14 / 15 | 5 / 6 | 5 / 6 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 6 / 6 | 18 / 18 | 15 / 15 | 6 / 6 | 6 / 6 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 0 / 5 | 0 / 6 | 3 / 18 | 2 / 15 | 1 / 6 | 2 / 6 | 0 / 1 |
Outcome results
None listed