E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Incurable recurrent or metastatic (R/M) HPV16-positive (HPV16+) tumors (e.g. oropharyngeal cancer, cervical, vulvar, vaginal, anal, penile cancer, etc.) |
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E.1.1.1 | Medical condition in easily understood language |
Incurable recurrent or spread cancer caused by the human papillomavirus type 16. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067821 |
E.1.2 | Term | Head and neck cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008229 |
E.1.2 | Term | Cervical cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047777 |
E.1.2 | Term | Vulvar cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061424 |
E.1.2 | Term | Anal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10046885 |
E.1.2 | Term | Vaginal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034299 |
E.1.2 | Term | Penile cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Cohort 1: To assess the safety and tolerability of IV administration of EI-201 as monotherapy in subjects with incurable R/M HPV16+ oropharyngeal and anogenital tumors and to select a starting dose of EI-201 for Cohort 2. Cohort 2: To assess the safety and tolerability of IV administration of EI-201 as add on to pembrolizumab in subjects with incurable R/M HPV16+ oropharyngeal and anogenital tumors. |
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E.2.2 | Secondary objectives of the trial |
Cohort 1: - To assess the immune response following EI-201 administration in subjects with incurable R/M HPV16+HPV16+ oropharyngeal and R/M HPV16+ anogenital tumors. - To assess the preliminary anti tumor activity of IV administration of EI-201 as monotherapy in subjects with incurable R/M HPV16+ oropharyngeal and anogenital tumors. Cohort 2: - To assess the immunogenicity of EI-201 as add on to pembrolizumab in subjects with incurable R/M HPV16+HPV16+ oropharyngeal HNSCC and R/M HPV16+ anogenital tumors. - To assess additional anti-cancer activity of EI-201 as add on to pembrolizumab in subjects with incurable R/M HPV16+HPV16+ oropharyngeal HNSCC and R/M HPV16+ anogenital tumors. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age greater than or equal to 18 years. 2. Cohort 1: Confirmed recurrent and/or metastatic (R/M) HPV16+ cancer (including oropharyngeal, cervical, vulvar, vaginal, anal, penile cancer) based on expression analysis of HPV type 16 in tumor tissue by HPV 16 ISH or HPV E1 PCR. Cancer must have progressed after at least 1 available standard therapy for incurable disease, or the subject is intolerant to or refuses standard therapy(ies) or has a tumor for which no standard therapy(ies) exists. Cohort 2: Confirmed R/M HPV16+ oropharyngeal cancer (based on expression of HPV type 16 in tumor tissue by HPV 16 ISH or HPV E1 PCR), and eligible for 1st line monotherapy pembrolizumab treatment OR subjects with confirmed incurable R/M anogenital HPV16+ cancer (cervical, anal, penile, vulvar, or vaginal cancer) confirmed by HPV 16 ISH or HPV E1 PCR. Maximum 2 previous systemic therapies with chemotherapy and/or targeted therapies for recurrent and/or metastatic disease, no prior aPD(L)-1, and a CPS>1. 3. Life expectancy of at least 12 weeks. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 5. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1; Eisenhauer et al, 2009). 6. Willing and able to give written informed consent. 7. Willing and able to attend the scheduled study visits and to comply with the study procedures, treatment schedule, laboratory test and other requirements of the study. 8. Subjects entering the study will need to consent to provide a tumor tissue sample (formalin fixed paraffin embedded blocks/slides less than 2 months old or older only upon approval by Sponsor) or a fresh biopsy before the first dose of the study treatment and a mandatory biopsy at Week 6 (Cohort 1) or Week 9 (Cohort 2) post start of treatment. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient. 9. Adequate hematologic function with: a) white blood cell (WBC) count ≥ 3,000 mm³ b) hemoglobin ≥ 9 g/dL c) platelets ≥ 75,000/mm³ d) lymphocyte count ≥500 cells/mm3 10. Adequate renal and hepatic function with: a) serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine-clearance ≥ 40 mL/minute using the Cockcroft-Gault formula b) alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST) ≤ 1.5 x ULN (subjects with liver metastasis can have up to 5 x ULN c) bilirubin < 2.0 mg/dL (except for subjects with Gilbert’s disease) 11. Adequate coagulation parameters with: a) Prothrombin international normalized ratio (INR) < 1.5 b) Partial thromboplastin time < 1.5 x ULN 12. Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. The Investigator shall review contraception methods and the time period that contraception must be followed. 13. A female subject 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) A WOCBP (defined as < 2 years after last menstruation or not surgically sterile) must have a negative highly sensitive pregnancy test at screening (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 study medication. The partners of subjects of childbearing potential must also apply contraceptive methods and are recommended not to donate sperm (APPENDIX C Note on Birth Control Methods).
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E.4 | Principal exclusion criteria |
Exclusion criteria to be assessed at Screening: 1. Subjects treated with any investigational agent within the past 4 weeks before the start of therapy are excluded. 2. Grade 3 or 4 peripheral neuropathy at time of screening. 3. Subjects with active or history of autoimmune disease or immune deficiency such as, but not restricted to, myasthenia gravis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, rheumatoid arthritis or multiple sclerosis, with the following exceptions: - endocrine autoimmune disorders (i.e., autoimmune hypothyroidism who are on thyroid replacement hormone, type 1 diabetes, Addison’s disease, etc.) - controlled eczema, psoriasis, lichen simples or vitiligo with dermatological manifestations only - rash < 10% of body surface area. 4. Subjects with serious intercurrent chronic or acute illness such as pulmonary [severe asthma or chronic obstructive pulmonary disease (COPD)], cardiac (New York Heart Association [NYHA] class III or IV), hepatic disease, renal insufficiency or other illness considered by the Investigator to constitute an unwarranted high risk for investigational drug treatment. 5. Subjects with known history of allergic reactions to contrast. 6. Subjects with significant psychiatric disabilities or seizure disorders. 7. Legal incapacity or limited legal capacity. 8. Subjects who have had a splenectomy. 9. Subjects with known hypersensitivity to any component of the Investigational Medicinal Product and/or pembrolizumab (Cohort 2). 10. Prior treatment with therapeutic HPV vaccines. Subjects may have received a preventive HPV vaccine. 11. Subjects who received an mRNA LNP based vaccine less than 30 days prior to start of the therapy. 12. Concurrent second malignancy other than non-melanoma skin cancer or controlled superficial bladder cancer. In the event of prior malignancies treated surgically, the subject must be considered NED (no evidence of disease) for a minimum of 3 years prior to enrollment. 13. Subjects on corticosteroid therapy > 10 mg prednisone (or equivalent) or other immunosuppressive agents such as azathioprine or cyclosporine A (but not limited to these) are excluded on the basis of potential immune suppression. 14. Presence of an active acute or chronic infection, including symptomatic urinary tract infection, human immunodeficiency virus (as determined by enzyme linked immunosorbent assay and confirmed by Western Blot) or viral hepatitis (as determined by hepatitis B antigen and hepatitis C serology). 15. Subject is pregnant, intending to become pregnant or is currently breast-feeding. 16. Subject testing positive for SARS-CoV-2 infection as detected by nasal real time polymerase chain reaction (RT-PCR) or subjects who have been in contact with SARS-CoV-2 infected individuals in the 2 weeks prior to first dosing of IMP. Subjects presenting any signs or symptoms of SARS-CoV-2 infection as detected at screening and/or baseline following careful physical examination (e.g., cough, fever, headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, etc.) will also be excluded. In addition, any other locally applicable standard diagnostic criteria may also apply to diagnose SARS-CoV-2 infection. Additional Criteria for Cohort 2: 17. Subjects with undifferentiated nasopharyngeal or sino-nasal cancers. 18. Subjects with symptomatic central nervous system (CNS) metastases must have been treated and metastases should be asymptomatic. 19. Chemotherapy, targeted small molecule therapy, or radiotherapy within 4 weeks prior to start of treatment with EI-201 for subjects with anogenital cancers. 20. Subjects who have received prior systemic therapy and/or active immunotherapy for HNSCC, such as antigen loaded dendritic cells, chimeric antigen receptor (CAR) T cells that target HPV antigens, or checkpoint inhibitors are excluded.
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohort 1: DLT, MTD, RP2D, SAEs, frequency and severity of AEs of escalating doses of EI-201 as monotherapy per dose level using NCI CTCAE 5.0. Cohort 2: DLT, MTD, RP2D, SAEs, AEs of EI-201 as add on to pembrolizumab using NCI CTCAE 5.0. Cohort 2: ORR (based on CR/PR using RECIST v1.1 and iRECIST for highest dose level only). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: At screening, day 1, day 8, day 15, day 22, day 29, day 43, day 50. Cohort 2: At screening, day 1, day 8, day 15, day 22, day 29, day 50, day 57, day 71, day 92, day 113, day 134, day 155, day 69, day 183. |
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E.5.2 | Secondary end point(s) |
Cohort 1: Number of immune responders to EI-201 per dose level. Cohort 1: ORR (based on CR/PR using RECIST v1.1 and iRECIST). Cohort 2: Immune response to EI-201 as add on to pembrolizumab at each visit. Cohort 2: - BOR based on CR, SD, PR, progressive disease (PD) and overall response at each visit by RECIST 1.1 and iRECIST - ORR (based on CR/PR using iRECIST and RECIST 1,1 for all dose levels). - Overall survival (OS). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: At screening, day 1, day 8, day 15, day 22, day 29, day 43, day 50. Cohort 2: At screening, day 1, day 8, day 15, day 22, day 29, day 50, day 57, day 71, day 92, day 113, day 134, day 155, day 69, day 183. |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
E.7.1.3.1 | Other trial type description |
Dose escalation and dose expansion |
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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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 | Yes |
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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |