IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 / KN-D18)

Study Overview
=================
Brief Summary
-----------------
Phase 3, multicenter, international, open-label, randomized, 2-arm trial investigating the safety and efficacy of IO102-IO103 in combination with pembrolizumab as first-line treatment for patients with previously untreated unresectable or metastatic (advanced) melanoma. Patients will be stratified on the basis of the following factors; Disease stage: Stage III (unresectable) and IV M1a-b versus stage IV M1c-d and BRAFV600 mutation status: mutated vs wild type. All patients will receive pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles (up to 2 years treatment). Patients randomized to IO102-IO103 dual-antigen, immunotherapeutic arm will also be given IO102-IO103 Q3W with an additional dose given during the induction period on Day 8 of cycles 1 and 2. IO102 IO103 will thereafter be administered subcutaneous every 3 weeks during the maintenance period. Each patient can be treated for a maximum of 37 administrations in total (up to 2 years of treatment). The primary objective is to investigate the efficacy of IO102-IO103 in combination with pembrolizumab (compared with pembrolizumab alone) in terms of progression free survival.

Official Title
-----------------
An Open-label, Randomized, Phase 3 Clinical Trial of IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Patients With Previously Untreated, Unresectable, or Metastatic (Advanced) Melanoma (IO102-IO103-013 / MK3475-D18)

Conditions
-----------------
Metastatic Melanoma, Unresectable Melanoma

Intervention / Treatment
-----------------
* Drug: IO102-IO103
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed stage III (unresectable) or stage IV melanoma, as per American Joint Committee on Cancer 8th edition guidelines not amenable to local therapy Patients are treatment naive, that is, no previous systemic anticancer therapy for unresectable or metastatic melanoma. For clarification, the following patients are eligible: Patients with BRAFV600 mutation-positive melanoma are eligible if treatment naive and without rapidly progressive disease as per investigators assessment. Documented BRAF V600 mutation status must be available from all patients prior to trial entry. Patients who have received previous adjuvant and/or neoadjuvant therapy with targeted therapy or immune therapy are eligible if administered the last dose at least 6 months before inclusion in this trial (randomization), and if relapse did not occur during active treatment or within 6 months of treatment discontinuation. At least 1 measurable lesion according to response evaluation criteria for solid tumors (RECIST v1.1) and confirmed by IRC. Provision of archival (obtained within 3 months), or newly acquired biopsy tissue not previously irradiated, and blood at screening for biomarker assessments. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Exclusion Criteria: Patients with known or suspected central nervous system (CNS) metastases or with the CNS as the only site of active disease are excluded with the following exception: • Patients with controlled (stable) brain metastases will be allowed to enroll (subject to baseline magnetic resonance imaging (MRI) confirmation). Controlled (stable) brain metastases are defined as those with no radiographic progression for at least 4 weeks after radiation and/or surgical treatment at the time of signed informed consent. Patients must have been off steroids for at least 2 weeks before signed informed consent and have no new or progressive neurological signs and symptoms. Patient has received previous radiotherapy within 2 weeks of start of trial treatment (visit 2). 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. Patients with BRAFV600-positive disease who are experiencing rapidly progressing disease and/or have received standard first-line therapy with BRAF and/or MEK inhibitor for unresectable or metastatic disease. Other protocol defined inclusion/exclusion criteria may apply.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised 1:1 to receive either dual-antigen IO102-IO103 in combination with pembrolizumab versus pembrolizumab alone
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IO102-IO103 + pembrolizumab<br>IO102-IO103 subcutaneous injections (85µg) every 3 weeks for a maximum 35 cycles (up to 2 years treatment). Additional dose given during the induction period on Day 8 of cycles 1 and 2. Each patient can be treated for a maximum of 37 administrations in total (up to 2 years treatment). Pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. | Drug: IO102-IO103<br>* IO102-IO103 comprises IDO peptide antigen (IO102) and PD-L1 peptide antigen (IO103) emulsified with adjuvant (Montanide ISA 51 VG) administered subcutaneously<br>Drug: Pembrolizumab<br>* Pembrolizumab administered intravenously<br>|
| Active Comparator: pembrolizumab<br>Pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles (up to 2 years treatment). | Drug: Pembrolizumab<br>* Pembrolizumab administered intravenously<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS defined as the time from randomization to the first documented disease progression ((based on Independent Review Committee in accordance with RECIST v1.1) or death from any cause. | Approximately 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR defined as the percentage of patients achieving a confirmed PR or CR. ORR will be determined by an IRC in accordance with RECIST v1.1. | Approximately 2.5 years | 
| Overall survival (OS) | OS defined as the time from randomisation until death from any cause. months. This will be determined by an IRC in accordance with RECIST v1.1. | Approximately 5.5 years | 
| Durable Objective response rate (DRR) | DRR is defined as the percentage of patients achieving a PR or CR > 6 months. This will be determined by an IRC in accordance with RECIST v1.1. | Approximately 3.5 years | 
| Complete response rate (CRR) | Percentage of patients with a visit response of CR, which will be determined by the IRC in accordance with RECIST v1.1. | Approximately 3.5 years | 
| Duration of response (DoR) | DoR will be measured from the date of first observed objective response until disease progression or death (whichever is earlier) (based on IRC). | Approximately 3.5 years | 
| Time to response (TTR) | TTR is defined as the time from the date of randomization to the date of first observed PR or CR (based on IRC). | Approximately 3.5 years | 
| Time to complete response (TTCR) | TTCR is defined as the time from the date of randomization to the date of first observed CR (based on IRC). | Approximately 3.5 years | 
| Disease control rate (DCR) | DCR is defined as the percentage of patients achieving a PR or CR or SD (based on IRC). | Approximately 3.5 years | 
| Incidence of e.g. AEs and SAEs (Safety and Tolerability) | Incidence of AEs and SAEs, and treatment related AEs and SAEs. Incidence of AEs causing discontinuation of trial treatment. | Approximately 3.5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pembrolizumab, Metastatic melanoma, Unresectable melanoma, Immunotherapy, Progression free survival, IO102-IO103