An open, dose-escalation Phase I/II study to assess the safety, immunogenicity and clinical activity of recPRAME + AS15 Antigen-Specific Cancer Immunotherapeutic as first-line treatment of patients with PRAME-positive metastatic melanoma.

INTERVENTION: Product Name: recPRAME(20µg)+AS15 Pharmaceutical Form: Powder and solvent for suspension for injection INN or Proposed INN: ‐ Other descriptive name: PD1/3‐PRAME‐His protein Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 20‐ Product Name: recPRAME(100µg)+AS15 Pharmaceutical Form: Powder and solvent for suspension for injection INN or Proposed INN: ‐ Other descriptive name: PD1/3‐PRAME‐His protein Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 100‐ Product Name: recPRAME(500µg)+AS15 Pharmaceutical Form: Powder and solvent for suspension for injection INN or Proposed INN: ‐ Other descriptive name: PD1/3‐PRAME‐His protein Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 500‐ CONDITION: First‐line treatment of patients with PRAME‐positive unresectable stage III or IV metastatic melanoma ; MedDRA version: 17.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): Secondary endpoints of the Phase I segment: ; •Safety endpoint: Occurrence of AEs and SAEs, including clinically significant abnormal hematological and biochemical values. ; •Immunogenicity endpoint: The anti‐PRAME cellular (T‐cell) response. ; The anti‐PRAME, anti‐protein D and anti‐CpG humoral response. ; •Clinical activity endpoint:Occurrence of objective clinical responses (complete (CR) or partial (PR) response). ; Occurrence of stable disease (SD). ; Occurrence of mixed response (MR). ; Time to Treatment Failure (TTF). ; Progression‐free survival (PFS). ; Overall survival (OS). ; The duration of response for patients with CR, PR or SD status. ; Secondary endpoints of the Phase II segment: ; •Safety endpoint:The secondary safety endpoints are identical to the secondary safety endpoints of the Phase I segment. ; •Clinical activity endpoint:The secondary clinical activity endpoints are identical to the secondary clinical activity endpoints of the Phase I segment except for CR/PR which are assessed as primary endpoints. ; •Immunogenicity endpoint:The secondary immunogenicity endpoints are the same as for the Phase I segment. ; As of Amendment 3, there will no longer be an active follow‐up of patients after discontinuation or completion of the study treatment. The study will end +/‐ 30 days after the last treatment administration. ; In addition, no more biological samples will be collected for protocol research purposes. For each biological sample already collected in the sope of this study and not tested yet, testing will not be performed by default, except if a scientific rationale remains relevant. Sampling for safety monitoring as per protocol will continue. Timepoint(s) of evaluation of this end point: •AEs/SAEs: up to 30 days after the last treatment administration. ; •Anti‐PRAME cellular and humoral response: at each timepoint samples will have been collected. ; •Clinical activity: Occurrence and duration of CR or PR, SD, MR, TTF, PFS, OS during the entire study. ; As of Amendment 3, there will no longer be an active follow‐up of patients after disccontinuation or completion of study treatment. The study will end +/‐ 30 days after the last injection. PRIMARY OUTCOME: Main Objective: Co‐primary objectives of the Phase I segment:; To characterize; •The occurrence of dose‐limiting toxicity.; •The anti‐PRAME humoral immune response; Co‐primary objectives of Phase II segment:; To characterize; •The clinical activity in terms of objective response.; •The occurrence of dose‐limiting toxicity; As of Amendment 3, there will no longer be an active follow‐up of patients after discontinuation or completion of study treatment. The study will end approximately 30 days after the last dose will be administered.; In addition, no more biological samples will be collected for protocol research purposes. For each biological sample already collected in the scope of the study and not tested yet, testing will not be performed by default, except if a scientific rationale remains relevant. Sampling for safety monitoring will continue. Primary end point(s): Co‐primary endpoints for the Phase I segment:; 1. Dose‐limiting toxicity endpoint; •Occurrence of dose‐limiting toxicity will be followed in all patients during the study treatment and until the end of follow‐up.; Criteria/definitions:; •An ASCI related or possibly ASCI related grade 3 or higher toxicity. Grade 3 myalgia, arthralgia, headache, fever, rigors/chills and fatigue (including lethargy, malaise and asthenia) should persist for 48 hours despite therapy in order to be considered as a dose limiting toxicity.; •An ASCI related or possibly ASCI related grade 2 or higher allergic reaction occurring within 24 hours following the ASCI administration..; •An ASCI related or possibly ASCI related decrease in renal function, with a creatinine clearance < 40 mL/min.; •An ASCI‐related or possibly ASCI‐related symptomatic and confirmed adrenal insufficiency. ; 2. Immunogenicity endpoint; •Anti‐PRAME humoral immune response after ASCI dose 4 (at Visit 5).; ; Co‐primary endpoints of the Phase II segment:; 1. Clinical activity endpoint; •Clinical activity in terms of objective clinical responses (CR and PR).; 2. Safety endpoint; •Occurrence of dose‐limiting toxicity will be followed in all patients during the study treatment and until the end of the follow‐up; As of Amendment 3, the follow‐up for clinical activity and safety will end +/‐ 30 days after the last treatment administration. Secondary Objective: For each dose tested in the Phase I segment and for the dose selected for the Phase II segment:; To characterize; •Additional clinical indicators of clinical activity in the overall study cohort and in the subgroup of patients who present the predictive MAGE‐A3 gene signature.; •Additional indicators of safety.; •The specific humoral and cellular immune response elicited by the recPRAME + AS15 ASCI.; As a result of the changes implemented in Amendment 3, specific humoral an cellular responses elicited by the recPRAME + AS15 ASCI will not be assessed further by default except if a scientific rationale remains relevant. Timepoint(s) of evaluation of this end point: Occurrence of dose limiting toxicity (Phase I and II) during study treatment/follow‐up: During the study treatment (up to 4 years) and until the end of a 1 year follow‐up.; ; Anti‐PRAME humoral immune response (Phase I): After the administration of dose 4 (Week 8); ; Clinical activity (Phase II) in terms of objective clinical responses (complete (CR) or partial (PR) response): At week 12, 23, 32, 54, years 1.5, 2, 2.5, 3, 3.5, 4 years + 1month, at 6 months after concluding visit, at 12 months after concluding visit.; As of Amendment 3, there will no longer be an active follow‐up for safety and clinical activity and the study will end +/‐ 30 days after the last treatment administration. ; In addition, no more biological samples will be collected for protocol research purposes. For each biological sample already collected in the scope of this study and not tested yet, testing will not be performed by default, except if a scientific rationale remains relevant. Sampling for safety monitoring as per protocol will continue. INCLUSION CRITERIA: 1.Male or female patient with histologically proven cutaneous melanoma. The stage of the disease is evaluated according to the classification of the American Joint Committee on Cancer, 2002. Phase I segment: All melanoma patients with stage IV M1b and stage IV M1c including completely resected stage IV patients but with the exception of stage IV M1c disease with serum lactate dehydrogenase (LDH) > 1.5 x Upper Limit of Normal (ULN) or with active involvement of the Central Nervous System (CNS). Note:Patients with a history of CNS involvement who have been treated by surgery or stereotaxic RT and whose disease has been under control for more than 6 months prior to the first administration of study treatment can be enrolled. Phase II segment: All melanoma patients with measurable, unresectable stage III melanoma including in‐transit metastasis (with (N3) or without (N2c) nodal metastasis) and stage IV M1a melanoma. The patient should have documented progressiv