A Single Arm Trial Evaluating the Efficacy and Safety of EVX-01 in Combination With Pembrolizumab in Adults With Unresectable or Metastatic Melanoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this single arm, multi-national clinical trial in patients with metastatic or unresectable melanoma is to evaluate the BOR and compare it to historical data on patients on anti-PD1 treatment with pembrolizumab alone.

Detailed Description
-----------------
Patients will initiate treatment with pembrolizumab at the start of the trial and receive up to 18 treatment cycles (approximately 2 years). Immunization with the EVX-01 will be initiated at Week 12. In total, 10 doses of EVX-01 will be administered intramuscularly, with 6 doses given two weeks apart and 4 booster doses at later time points.

Official Title
-----------------
An Open Label, Single Arm Trial Evaluating the Efficacy and Safety of EVX-01 in Combination With Pembrolizumab in Checkpoint Inhibitor Treatment naïve Adults With Unresectable or Metastatic Melanoma

Conditions
-----------------
Melanoma Stage III, Melanoma Stage IV

Intervention / Treatment
-----------------
* Drug: EVX-01
* Drug: Pembrolizumab 25 MG/ML


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be at least 18 years of age on day of signing informed consent. Histologically confirmed, and not amenable to local therapy, metastatic or unresectable melanoma Stage III or Stage IV, as per AJCC 8th ed. staging system. Patient may not have a diagnosis of uveal or ocular melanoma. Patients must be treatment naïve to checkpoint inhibitor (CPI) therapy Patients must have testing for a BRAF mutation prior to study entry. Note: Patients with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy as first-line systemic therapy and be eligible for this study 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 study as first line treatment if they meet the following additional criteria: i. LDH < local ULN, ii. No clinically significant tumor related symptoms in the judgment of the investigator, and iii. Absence of rapidly progressing metastatic melanoma in the judgment of the investigator Have measurable disease per RECIST 1.1 as assessed by the local site investigator within 4 weeks prior to the first visit. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Patients must be willing and able to provide fresh or frozen tumor tissue from an unresectable or metastatic site of disease for neoepitope and biomarker analyses. If a sufficient amount of tumor tissue from an unresectable or metastatic site is not available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue. In addition, participants may provide additional biopsy at the time of discontinuation due to progression. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: 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 anti-cancer therapy including investigational agents within 4 weeks prior to treatment. Has received prior radiotherapy within 2 weeks of start of study 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. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines are allowed.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EVX-01 in combination with pembrolizumab<br>EVX-01 is administered im. Pembrolizumab is administered according to label | Drug: EVX-01<br>* Investigational drug given in combination with standard of care<br>Drug: Pembrolizumab 25 MG/ML<br>* Standard of care<br>* Other names: Keytruda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the best overall response (BOR) | Composite of a BOR of complete response (CR) or PR for patients with SD at the time of first EVX-01 administration and a BOR of CR for patients with PR at the time of first EVX-01 administration, within 2 years of treatment with pembrolizumab, as per RECIST 1.1 criteria | Measurements at Baseline through study completion (up to 102 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in overall response rate | Overall response rate, defined as the proportion of the patients who have best response as CR or PR assessed 2 years after initiation of treatment with pembrolizumab, as per RECIST 1.1 criteria | Measurements at Baseline through study completion (up to 102 weeks) | 
| Change in progression free survival (PFS) | PFS in patients with an assessment of SD, PR, or CR at the time of first EVX-01 administration, assessed 2 years after initiation of treatment with pembrolizumab and defined as the time from the first EVX-01 administration to the first documented disease progression per RECIST 1.1. criteria or death due to any causes, whichever occurs first | Measurements at Baseline through study completion (up to 102 weeks) | 
| Change in overall survival (OS) | OS assessed 2 years after initiation of treatment with pembrolizumab and defined as the time from initiation of treatment of pembrolizumab to death due to any cause | Measurements at Baseline through study completion (up to 102 weeks) | 
| Number, type and severity of adverse events (AEs) and serious adverse events (SAEs) | Number, type and severity of adverse events (AEs) and serious adverse events (SAEs) to evaluate the safety of EVX-01 in patients with metastatic or unresectable melanoma on pembrolizumab treatment | Measurements at Baseline through study completion (up to 102 weeks) | 
| Immunologic response induced by EVX-01 | Activation and level of neoepitope specific CD4+ and CD8+ T-cells before, during and after EVX-01 immunization | Measurements at Baseline through study completion (up to 102 weeks) | 
| Percentage of patients in which EVX-01 is generated, produced, and administered | Percentage of patients in which EVX-01 is generated, produced, and administered to evaluate the manufacturing feasibility of EVX-01 | From tumor biopsy sampling to first dose of EVX-01 (up to 16 weeks) |