| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with incurable advanced or metastatic solid tumor malignancy for whom no treatment options exist and who have tumor lesion that is accessible for intratumoral injection of CyPep-1. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects diagnosed with an advanced or metastatic solid tumor. Currently, there is no standard therapy available to treat this tumor. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of IT administration of CyPep-1 as monotherapy and in combination with pembrolizumab.
To identify the recommended phase II dose (RP2D) of CyPep-1 as monotherapy and in combination with pembrolizumab. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in combination with pembrolizumab, in the injected lesions.
To characterize the pharmacokinetics (PK) of CyPep-1.
Additional Exploratory objectives
To assess the preliminary anti-tumor efficacy of CyPep-1, as monotherapy and in combination with pembrolizumab, in all lesions (injected lesions and non-injected lesions combined).
To assess survival after treatment with CyPep-1 as monotherapy and in combination with pembrolizumab.
To assess the immune modulating properties of treatment with CyPep-1 as monotherapy and in combination with pembrolizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
MAIN Criteria: Limited characters
Phase I and Phase IIa Arm A:
1. Histologically confirmed diagnosis of advanced or metastatic solid tumor malignancy that is refractory to SoC treatment or for which there is no appropriate standard therapy. Metastatic deposits of tumors for which IT injections may be performed are eligible. Pure cutaneous infiltrations are ineligible.
2. 1-3 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 treated with CyPep-1.
Arm C:
3. Confirmation of the presence of at least 1 liver metastasis by imaging.
4. Disease progression during or after one or more prior SoC systemic anti cancer therapy for metastatic disease or progression during or within 6 months of receiving adjuvant therapy. If subjects, are deemed not appropriate for systemic anti-cancer therapy for metastatic disease or if they refuse it, they may be eligible after investigator discussion with Sponsor and medical monitor for approval.
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 ≥ 1 cm as measured by CT scan or 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 bleeding risk.
Phase I and Arms A and C in addition:
7. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy at screening and at Week 6.
8. Age ≥ 18 years.
9. Estimated life expectancy of at least 3 months.
10. Eastern Cooperative Oncology Group Performance Status of 0 or 1
11. 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.
12. Ability to give written informed consent and to comply with the protocol.
13. All subjects of childbearing potential must have a negative highly sensitive pregnancy test at screening and agree to use highly effective method for contraception according to the EU CTFG guidance from time of signing the 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.
14. Adequate bone marrow, liver, and renal function
For Arm B:
15. The participant (or LAR) provides written informed consent for the trial.
16. Age 18 years
17. Participant with histologically confirmed diagnosis of advanced or metastatic solid tumor malignancy that is refractory to SoC treatment or for which there is no appropriate standard therapy. Metastatic deposits of tumors for which IT injections may be performed are eligible. Pure cutaneous infiltrations are ineligible.
18. Subjects must have progressed if on treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the listed in the protocol.
19. 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 IMP.
20. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP)
b) A WOCBP must have negative highly sensitive pregnancy test at screening and follow the EU CTFG contraceptive guidance from signing the ICF until at least 120 days after the last administration of IMP. The partners of subjects with childbearing potential must also apply contraceptive methods, and are recommended not to donate sperm.
21. 1-3 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.
22. Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy at screening and at Week 6.
23. Have an ECOG performance status of 0 to 1.
24. Have adequate organ function as defined in the protocol.
25. 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.
26. Estimated life expectancy of at least 3 months.
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| E.4 | Principal exclusion criteria |
MAIN Criteria: Limited characters
Phase I and Arm A and C:
1. prior treatment(s) with compounds delivered by IT injection to the to-be injected lesion(s), including investigational agents.
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
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.
7. Clinical evidence of an active second malignancy that is progressing or requires active treatment, except for curatively treated early stage carcinomas or non-melanoma skin cancer.
8. Active autoimmune disease requiring immunosuppressive therapy.
9. Any condition requiring continuous systemic treatment with either corticosteroids
or other immunosuppressive agents within 2 weeks prior to first dose of CyPep-1.
10. Abnormal or clinically significant coagulation parameters: PT-INR + APTT
11. Subjects on anticoagulants for whom temporarily stop and start, supported by low molecular weight heparin (or other anticoagulation therapy) during treatment period, is not an option
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 CD4 are present.
15. Central nervous system metastasis that is symptomatic or progressing or that requires current therapy
16. QTcF > 480 ms, history of long or short QT syndrome, Brugada syndrome, or known history of QTc 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 for Arm C:
19. Subject is a candidate for hepatic surgery or local regional therapy of liver metastases with curative intent.
20. More than 1/3 of the liver is estimated to be involved with metastases.
21. There is invasion by cancer into the main blood vessels.
22. Subject is currently receiving or has received liver metastatic-directed therapy less than 4 weeks prior to enrolmentor hepatic surgery.
Arm B:
Some criteria for arm B correspond to criteria for Phase I and Arm A and C. Due to the character limitation only a reference to these sections is listed below.
23. 17
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 and was discontinued from that treatment due to a Grade 3 or higher 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.
27. 5
28. 1
29. 6
30. Ongoing pembrolizumab-related toxicity event(s) as per TLT definition.
31. 2
32. Has had an allogeneic tissue/solid organ transplant.
33. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 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 carcinomas or non-melanoma skin cancer.
35. Has known active CNS metastases and/or carcinomatous meningitis
36. Has severe hypersensitivity 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
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. Known active human immunodeficiency virus (HIV). Subject normal D4 levels are eligible.
41. Has a known history of Hepatitis B or known active Hepatitis C virus infection.
42. 18
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
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints
- Type and number of adverse events (AEs) according to National Cancer Institute (NCI) – Common Terminology Criteria for Adverse Events (CTCAE) criteria v5.0, and additional safety parameters of CyPep-1 as monotherapy and in combination with pembrolizumab.
- Dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) for determination of RP2D of CyPep-1 as monotherapy and treatment-limiting toxicities (TLTs) of CyPep-1 in combination with pembrolizumab.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- AE's will be evaluated at each visit
- The DLT observation period for each dose level will be 6 weeks (5 weeks of trial treatment and 1 week of safety follow-up).
After completion of Phase I, all results will be evaluated by the DEC. The DEC will confirm the MTD or RP2D (in case the MTD is not reached).
The TLT observation period is 6 weeks. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
- Objective response rate (ORR) at RP2D in injected lesions, defined by complete and partial responses, according to immune Response Evaluation Criteria in Solid Tumors (iRECIST).
- Time to and duration of response and duration of stable disease.
- The plasma concentration time profile of CyPep-1 and, if detectable, the derived PK parameters (i.e., area under the curve [AUC], peak plasma concentration [Cmax], time to reach Cmax [tmax], systemic clearance (CL), elimination half-life (t1/2) and volume of distribution [VD]).
Exploratory endpoints
- ORR in all lesions (injected lesions and non-injected lesions combined, per iRECIST).
- Progression-free survival (PFS) based on all lesions.
- Overall survival (OS).
- The relative change in number of tumor infiltrating CD8+ T-cells in the injected and, whenever available, non-injected tumor biopsies.
- The association between the relative change in tumor infiltrating CD8+ T-cells and response rate.
- The change in T-cell receptor (TCR) clonality levels in peripheral blood.
- Changes in the tumor microenvironment (injected and, whenever available, non-injected tumor biopsies) via expression of selected candidate immune markers: CD3, CD4, CD8, programmed death ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), dendritic cell markers (CD80, CD86), immune suppressive cell markers (anti-FoxP3 for regulatory T-cells, anti-CD68 antibody for macrophages, anti-CD14 for monocytes, anti-CD15 for granulocytes, anti-CD56 for NK cells).
- Changes in the levels of peripheral blood cytokines (IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-15, TNF-α, TGF-β).
- Peripheral blood phenotyping of selected immune cell markers.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Clinical efficacy of CyPep-1 monotherapy and in combination with pembrolizumab will be measured by radiologic assessments (e.g., ultrasound, CT, MRI) every 8 weeks, starting from screening (baseline)
-Blood draw: At screening, during treatment visits until end follow-up visits.
- Tumor biopsies at screening and week 6 during cycle 1 and potentially in subsequent cycles (not mandatory) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| TCR clonality is tested with DNA |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial is defined as the last subject’s last visit. For the purposes of data summarization, data analyses will be performed after the last enrolled subject has completed 3 months of trial participation. Subjects may still be in the trial at the time of data summarization, as all subjects may continue to participate until disease progression, unacceptable toxicity, or discontinuation for any other reason. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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