| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| unresectable or metastatic melanoma |
| melanoma non resecabile o metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| a type of skin tumor |
| un tipo di tumore della pelle |
|
| 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 if EVX-01 improves the best overall response (BOR) in patients with an initial assessment of stable disease (SD) or partial response (PR) after initiating pembrolizumab treatment, as compared to historical outcomes with pembrolizumab alone in metastatic or unresectable melanoma |
| Valutare se EVX-01 migliora la migliore risposta complessiva (BOR) in pazienti con una valutazione iniziale di malattia stabile (SD) o risposta parziale (PR) dopo l’inizio del trattamento con pembrolizumab, rispetto agli esiti storici con pembrolizumab in monoterapia nel melanoma metastatico o non resecabile. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate if EVX-01 in combination with pembrolizumab improves the overall response rate, as compared to historical outcomes with pembrolizumab alone in metastatic or unresectable melanoma
-To evaluate if EVX-01 improves the progression free survival (PFS) in patients with an initial assessment of SD or PR after initiating pembrolizumab treatment, as compared to historical outcomes with pembrolizumab alone in metastatic or unresectable melanoma
-To evaluate if EVX-01 in combination with pembrolizumab improves the overall survival (OS), as compared to historical outcomes with pembrolizumab alone in metastatic or unresectable melanoma
-To evaluate the safety of EVX-01 in patients with metastatic or unresectable
melanoma on pembrolizumab treatment
-To evaluate the immunologic response induced by EVX-01
-To evaluate the feasibility of manufacturing EVX-01 |
- Valutare se EVX-01 in combinazione con pembrolizumab migliora il tasso di risposta complessiva rispetto agli esiti storici con pembrolizumab in monoterapia nel melanoma metastatico o non resecabile
- Valutare se EVX-01 migliora la sopravvivenza libera da progressione (PFS) in pazienti con una valutazione iniziale di SD o PR dopo l’inizio del trattamento con pembrolizumab, rispetto agli esiti storici con pembrolizumab in monoterapia nel melanoma metastatico o non resecabile
- Valutare se EVX-01 in combinazione con pembrolizumab migliora la sopravvivenza complessiva (OS), rispetto agli esiti storici con pembrolizumab in monoterapia nel melanoma metastatico o non resecabile
- Valutare la sicurezza di EVX-01 in pazienti con melanoma metastatico o non resecabile durante il trattamento con pembrolizumab
- Valutare la risposta immunologica indotta da EVX-01
-Valutare la fattibilità della produzione di EVX-01 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient (or legally acceptable representative if applicable) provides written
informed consent for the trial.
2. Be ³ 18 years of age on day of signing informed consent.
3. Histologically confirmed, and not amenable to local therapy, metastatic or
unresectable melanoma Stage III or Stage IV, as per AJCC 8th ed. staging system.
a. Patient may not have a diagnosis of uveal or ocular melanoma.
b. Patients must be treatment naïve to checkpoint inhibitor (CPI) therapy
c. Patients must have testing for a BRAF mutation prior to trial entry. Patients
with BRAF V600E mutant melanoma may have received prior BRAF
inhibitor therapy as first-line systemic therapy and be eligible for this trial as
second line treatment. At the discretion of the investigator, patients with
BRAF V600E mutant melanoma who have NOT received a BRAF inhibitor
are also eligible for this trial as first-line treatment if they meet the following
additional criteria:
i. LDH < local ULN at screening
ii. No clinically significant tumor related symptoms in the judgment of the investigator
iii. Absence of rapidly progressing metastatic melanoma in the judgment of the investigator
4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator
within 4 weeks prior to trial allocation. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
5. Patients must be willing and able to provide fresh tumor tissue from an unresectable or metastatic site of disease for neoepitope and biomarker analyses.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 4
weeks prior to trial allocation.
7. A male patient 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 treatment.
Contraceptive use by men should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
8. A female patient 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 who agrees to follow contraceptive guidance during the treatment
period and for at least 120 days after the last dose of trial treatment.
Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
9. Absence of any condition hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
10. Have adequate organ function . Specimens must be collected within 10 days prior to trial allocation.
11. Human immunodeficiency virus (HIV) infected patients must be on anti-retroviral
therapy (ART) and have a well-controlled HIV infection/disease defined as:
a. Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of
screening
b. Patients on ART must have achieved and maintained virologic suppression
defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of
qualification (below the limit of detection) using the locally available assay at the
time of screening and for at least 12 weeks prior to trial allocation
c. Patients on ART must have been on a stable regimen, without changes in drugs or
dose modification, for at least 4 weeks prior to trial allocation
12. Patients who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior
to trial allocation.
13. Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening.
|
1. The patient (or legally acceptable representative if applicable) provides written
informed consent for the trial.
2. Be ³ 18 years of age on day of signing informed consent.
3. Histologically confirmed, and not amenable to local therapy, metastatic or
unresectable melanoma Stage III or Stage IV, as per AJCC 8th ed. staging system.
a. Patient may not have a diagnosis of uveal or ocular melanoma.
b. Patients must be treatment naïve to checkpoint inhibitor (CPI) therapy
c. Patients must have testing for a BRAF mutation prior to trial entry. Patients
with BRAF V600E mutant melanoma may have received prior BRAF
inhibitor therapy as first-line systemic therapy and be eligible for this trial as
second line treatment. At the discretion of the investigator, patients with
BRAF V600E mutant melanoma who have NOT received a BRAF inhibitor
are also eligible for this trial as first-line treatment if they meet the following
additional criteria:
i. LDH < local ULN at screening
ii. No clinically significant tumor related symptoms in the judgment of the investigator
iii. Absence of rapidly progressing metastatic melanoma in the judgment of the investigator
4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator
within 4 weeks prior to trial allocation. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
5. Patients must be willing and able to provide fresh tumor tissue from an unresectable or metastatic site of disease for neoepitope and biomarker analyses.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 4
weeks prior to trial allocation.
7. A male patient 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 treatment.
Contraceptive use by men should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
8. A female patient 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 who agrees to follow contraceptive guidance during the treatment
period and for at least 120 days after the last dose of trial treatment.
Contraceptive use by women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
9. Absence of any condition hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
10. Have adequate organ function . Specimens must be collected within 10 days prior to trial allocation.
11. Human immunodeficiency virus (HIV) infected patients must be on anti-retroviral
therapy (ART) and have a well-controlled HIV infection/disease defined as:
a. Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of
screening
b. Patients on ART must have achieved and maintained virologic suppression
defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of
qualification (below the limit of detection) using the locally available assay at the
time of screening and for at least 12 weeks prior to trial allocation
c. Patients on ART must have been on a stable regimen, without changes in drugs or
dose modification, for at least 4 weeks prior to trial allocation
12. Patients who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior
to trial allocation.
13. Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening. |
|
| E.4 | Principal exclusion criteria |
-A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- 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., CTLA-4, OX 40, CD137).
-Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to first dose of trial treatment.
- Has received prior radiotherapy within 2 weeks prior to first dose of trial treatment. Patients 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.
-Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial intervention.
-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.
-Has had an allogeneic tissue/solid organ transplant.
-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 to the first dose of trial treatment.
-Has a known additional malignancy that is progressing or has required active treatment within the past 3 years prior to trial allocation.
- Known CNS metastases and/or carcinomatous meningitis.
- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
-Has an active autoimmune disease that has required systemic treatment in past 2 years prior to trial allocation (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.
-Has a history of (non-infectious) pneumonitis / interstitial lung disease that required
steroids or has current pneumonitis / interstitial lung disease.
- Has an active infection requiring systemic therapy.
- HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
-Has a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the trial.
|
-A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- 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., CTLA-4, OX 40, CD137).
-Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to first dose of trial treatment.
- Has received prior radiotherapy within 2 weeks prior to first dose of trial treatment. Patients 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.
-Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial intervention.
-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.
-Has had an allogeneic tissue/solid organ transplant.
-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 to the first dose of trial treatment.
-Has a known additional malignancy that is progressing or has required active treatment within the past 3 years prior to trial allocation.
- Known CNS metastases and/or carcinomatous meningitis.
- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
-Has an active autoimmune disease that has required systemic treatment in past 2 years prior to trial allocation (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.
-Has a history of (non-infectious) pneumonitis / interstitial lung disease that required
steroids or has current pneumonitis / interstitial lung disease.
- Has an active infection requiring systemic therapy.
- HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
-Has a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Composite of a BOR of CR or PR for patients with SD at the time of EVX-01 administration and a BOR of CR for patients with PR at the time of EVX-01 administration, during 24 months of treatment with pembrolizumab, as per RECIST 1.1 criteria. |
| Endpoint composito di una BOR di risposta completa (CR) o PR per pazienti con SD al momento della prima somministrazione di EVX-01 e una BOR di CR per i pazienti con PR al momento della prima somministrazione di EVX-01, entro 2 anni dal trattamento con pembrolizumab, secondo i criteri RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final analysis on the primary endpoint will be conducted after all patients have either completed the approximately two-year treatment with pembrolizumab or have been censored due to an event before. |
| L'analisi finale sull'endpoint primario sarà condotta dopo che tutti i pazienti hanno completato il trattamento di circa due anni con pembrolizumab o sono stati censurati a causa di un evento precedente |
|
| E.5.2 | Secondary end point(s) |
•Overall response rate, defined as the proportion of the patients in the
analysis population who have best response as CR or PR assessed 24
months after initiation of treatment with pembrolizumab as per RECIST
1.1 criteria
• PFS assessed 24 months after initiation of treatment with
pembrolizumab and defined as the time from initiation of pembrolizumab
treatment to the first documented disease progression per RECIST 1.1.
criteria or death due to any causes, whichever occurs first
• OS, assessed 24 months after initiation of treatment with
pembrolizumab and defined as the time from initiation of treatment of
pembrolizumab to death due to any cause
• Number, type and severity of AEs and SAEs
• Level of immunologic response toward EVX-01 measured by CD4+ and
CD8+ neoepitope specific lymphocytes, assessed throughout dosing with
EVX-01 |
•Overall response rate, defined as the proportion of the patients in the
analysis population who have best response as CR or PR assessed 24
months after initiation of treatment with pembrolizumab as per RECIST
1.1 criteria
• PFS assessed 24 months after initiation of treatment with
pembrolizumab and defined as the time from initiation of pembrolizumab
treatment to the first documented disease progression per RECIST 1.1.
criteria or death due to any causes, whichever occurs first
• OS, assessed 24 months after initiation of treatment with
pembrolizumab and defined as the time from initiation of treatment of
pembrolizumab to death due to any cause
• Number, type and severity of AEs and SAEs
• Level of immunologic response toward EVX-01 measured by CD4+ and
CD8+ neoepitope specific lymphocytes, assessed throughout dosing with
EVX-01 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis on the sec. endpoint will be conducted after all patients have either completed the approximately two-year treatment with pembrolizumab or have been censored due to an event before. |
| The final analysis on the sec. endpoint will be conducted after all patients have either completed the approximately two-year treatment with pembrolizumab or have been censored due to an event before. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity |
| Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| In aperto, a braccio singolo |
| Open label, single arm |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United States |
| France |
| Spain |
| Italy |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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