Trial: A Randomized, Phase 2/3 Study to Invest…

Trial Details

Sponsor: Replimune Inc. (industry)

Phase: 2/3

Start date: Dec. 17, 2024

Planned enrollment: 280

Trial ID: NCT06581406

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: RP2

Overview

RP2 is an investigational, intratumorally delivered, genetically modified herpes simplex virus type 1 (HSV‑1) oncolytic immunotherapy being developed by Replimune. Early human data come from an open‑label phase 1 study (NCT04336241) testing RP2 alone and with nivolumab, including a metastatic uveal melanoma cohort; a randomized phase 2/3 trial in checkpoint‑inhibitor–naïve metastatic uveal melanoma opened in late 2024 (NCT06581406). (ascopubs.org)

Mechanism of action

Backbone: replication‑competent HSV‑1 modified for tumor‑selective lysis and enhanced cell‑to‑cell spread via deletion of ICP34.5/ICP47 and insertion of a fusogenic gibbon ape leukemia virus glycoprotein (GALV‑GP‑R−). This promotes direct oncolysis and immunogenic tumor cell death. (jitc.biomedcentral.com)
Transgenes: human GM‑CSF to recruit/activate antigen‑presenting cells, and an anti‑CTLA‑4 antibody‑like molecule to locally block CTLA‑4 and potentiate T‑cell priming; RP2 can be combined systemically with anti‑PD‑1 therapy (e.g., nivolumab). (jitc.biomedcentral.com)
Administration/dosing used in phase 1: intratumoral 1×10^6 PFU/mL once, then up to seven additional doses at 1×10^7 PFU/mL (≤10 mL per treatment day), every two weeks; with or without nivolumab. (ascopubs.org)

Efficacy

Metastatic uveal melanoma (previously treated population, phase 1, n=17; RP2 mono n=3; RP2+nivolumab n=14):
- Overall response rate: 29.4% (5/17; 1 with RP2 monotherapy; 4 with RP2+nivolumab). Responses occurred in liver, lung, and bone metastases. (ir.replimune.com)
- Disease control rate: 58.8% (ASCO 2024 abstract). (ir.replimune.com)
- Median duration of response at cutoff: 11.47 months (range 2.78–21.22), with responses ongoing (Society for Melanoma Research 2023 presentation). Earlier interim ASCO 2023 reporting showed ORR 28.6% among evaluable patients and median DOR 5.8 months at an earlier cutoff. (ir.replimune.com)

Ongoing randomized study (RP2‑202/REVEAL; NCT06581406): RP2+nivolumab versus ipilimumab+nivolumab in immune checkpoint–inhibitor–naïve metastatic uveal melanoma; planned enrollment ~280; start December 2024; estimated primary completion January 2030. (cdek.pharmacy.purdue.edu)

Context: In prior studies, nivolumab+ipilimumab achieved ORR ~18% in metastatic uveal melanoma, underscoring the unmet need. (pubmed.ncbi.nlm.nih.gov)

Safety

Across the phase 1 uveal melanoma cohort (RP2 alone or with nivolumab):
- Most common treatment‑related adverse events (primarily grade 1–2): pyrexia, chills, fatigue, hypotension, pruritus. (ir.replimune.com)
- Grade 3 events: hypotension in two patients receiving RP2+nivolumab; no grade 4–5 treatment‑related events reported at the time of the interim analyses. (ascopubs.org)

HealthScout AI Analysis

Goal: To determine whether intratumoral RP2 combined with nivolumab improves clinical outcomes versus the standard checkpoint inhibitor combination of ipilimumab plus nivolumab in immune checkpoint inhibitor–naïve metastatic uveal melanoma.

Patients: Adults ≥18 years with histologically or cytologically confirmed metastatic uveal melanoma not amenable to surgery, ECOG 0–1, life expectancy >6 months, LDH ≤2×ULN, adequate organ function, and at least one measurable, injectable lesion ≥1 cm (≥1.5 cm short axis for lymph nodes) suitable for serial RP2 injections. Key exclusions include any prior immune checkpoint inhibitor exposure for uveal melanoma, active CNS involvement, active or uncontrolled infections including HBV/HCV/HIV, significant herpetic disease or prior oncolytic virus exposure, need for anti‑herpetic antivirals, active autoimmune disease requiring systemic therapy, recent major surgery, recent systemic anticancer therapy or radiotherapy, recent investigational agents, and immunosuppressive corticosteroid use >10 mg prednisone equivalent.

Design: Randomized, open-label, active-controlled, phase 2/3 treatment trial with two parallel arms and blinded independent central review for radiographic endpoints. Approximately 280 patients will be randomized to receive either RP2 plus nivolumab or ipilimumab plus nivolumab.

Treatments: Test arm: RP2 plus nivolumab. RP2 is an investigational, intratumoral oncolytic immunotherapy based on replication‑competent HSV‑1 engineered to enhance oncolysis and antitumor immunity. It expresses GALV‑GP‑R− (fusogenic glycoprotein), GM‑CSF, and an anti‑CTLA‑4–like molecule to promote tumor cell lysis, antigen presentation, and local checkpoint blockade. Early phase 1 data in metastatic uveal melanoma and other solid tumors have shown manageable safety and objective responses, including in PD‑1–refractory settings, with signals of systemic immune activation. Control arm: Ipilimumab plus nivolumab, a standard dual checkpoint inhibitor regimen targeting CTLA‑4 and PD‑1, respectively.

Outcomes: Co-primary endpoints are overall survival and progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints include safety and tolerability (incidence of treatment-emergent adverse events), overall response rate, and disease control rate by BICR per RECIST v1.1. Time-to-event endpoints are followed from Day 1 up to 3 years after last dose; safety is collected through 100 days after last dose.

Burden on patient: Moderate. Patients require serial image-guided intratumoral injections of RP2 in the experimental arm and mandatory tumor biopsies, adding procedure-related visits and risks such as pain, bleeding, and infection. Radiographic assessments approximately every 12 weeks and routine labs align with typical metastatic melanoma practice, but on-treatment monitoring for viral therapy–related adverse events and herpetic precautions may increase visit frequency early in therapy. The control arm involves standard intravenous checkpoint infusions and scheduled imaging, representing lower procedural burden than the intratumoral approach. Overall travel and visit load will be greater for those receiving RP2 due to injection sessions and biopsy requirements.

Last updated: Oct 2025

Eligibility

Show Criteria

Key Inclusion Criteria:

* Patients who are 18 years of age or older at the time of signed informed consent.

* Patients with confirmed diagnosis of metastatic Uveal melanoma not amenable to surgical resection.

* Has at least 1 measurable and injectable tumor of ≥ 1 cm in longest diameter (≥ 1.5 cm in the shortest axis for a lymph node \[LN\]) that is amenable to serial RP2 injections.

* Must be willing to provide tumor biopsy samples.

* LDH ≤ 2 × upper limit of normal (ULN).

* Has adequate hematologic, hepatic and renal function

* Prothrombin time (PT) ≤ 1.5 × ULN (or international normalization ratio \[INR\] ≤ 1.3) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

* Life expectancy of \> 6 months as estimated by the Investigator.

Key Exclusion Criteria:

* Any exposure to immune checkpoint inhibitor (ICIs) since the time of first being diagnosed with uveal melanoma.

* Known acute or chronic Hepatitis B or C infection or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.

* Current active significant herpetic infections or prior complications of HSV-1 infection.

* Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.

* Major surgery ≤ 2 weeks prior to the first dose of study intervention.

* Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy.

* Active, known, or suspected autoimmune disease requiring systemic treatment.

* Prior treatment with an oncolytic virus.

* Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).

* Systemic anticancer therapy or prior radiotherapy within 2 weeks of the first dose.

* Has received Investigation agent within 4 weeks or 5 half-lives (whichever longer) prior to the first dose.

* Conditions requiring treatment with immunosuppressive doses (\> 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment.

Trial Details

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: RP2

Overview

Mechanism of action

Efficacy

Safety

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (24)

HonorHealth Research Insisute

Stanford Cancer Institute

The Angeles Clinic and Research Institute

UC San Diego Moores Cancer Center

University of California Los Angeles

The Melanoma & Skin Cancer Institute

Georgetown University Medical Center

Sylvester Comprehensive Cancer Center

Emory Winship Cancer Institute

Northwestern Memorial Hospital

University of Chicago Medical Center

University of Iowa

Massachusetts General Hospital

Memorial Sloan Kettering Cancer Center

Duke University Medical Center

The Ohio State University

Thomas Jefferson University

UPMC Hillman Cancer Center

Sarah Cannon Research Institute

The West Clinic, PLLC dba West Cancer Center

Vanderbilt Ingram Cancer Center (Henry-Joyce Cancer Clinic)

The University Of Texas Md Anderson Cancer Center

UT Southwestern Medical Center

University Of Wisconsin Carbone Cancer Center - University Hospital