RP2 for Metastatic uveal melanoma

Inclusion criteria

• {"criterion_text":"- Patients who are 18 years of age or older at the time of signed informed consent.\n- 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, based on central laboratory testing. Note: Patients who are on therapeutic doses of anticoagulants may be eligible on a case-by-case basis following discussion with the Medical Monitor, if their pretreatment target INR is <2.5 and if such treatments can be interrupted or dose decreased as medically appropriate around the time of RP2 injections and protocol-specified biopsies. Patients on prophylactic doses of anticoagulants must have such agents temporarily held for an appropriate duration before and after each RP2 injection and/or protocol-specified biopsies. For patients requiring deep/visceral injection(s) of RP2, the INR must be ≤1.5 at the time of each injection.\n- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.\n- Female and male patients who meet the following criteria: a) Females patients are eligible if not pregnant or breastfeeding and if one of the following applies 1) is a women of non-child bearing potential (WNCBP) OR 2) is a woman of childbearing potential (WOCBP) and must agree to use a highly effective contraception method during the treatment period and for at least (a) 90 days after last dose of RP2, or (b) 5 months after the last dose of nivolumab, (c) or 3 months after the last dose of ipilimumab, whichever is longer. b) Male patients are eligible to participate if they agree to the following during the study treatment period and for at least 90 days after the last dose of RP2: refrain from donating fresh unwashed semen plus either be abstinent from intercourse where pregnancy can occur (abstinent on a long term and persistent basis) and agree to remain abstinent OR must agree to use external condom and should also advise their partner to use a highly effective method of contraception (Section 10.4.2) as a condom may break or leak. Note: Patients must agree to follow the manufacturer’s most current prescribing information regarding contraceptive requirements for nivolumab and ipilimumab. Definitions, highly effective contraception methods, and barrier guidance are provided in Section 10.4.\n- Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG within 72 hours before the first dose of any study intervention and a negative urine pregnancy test predose on the day of Dose 1.\n- Signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.\n- Patients with histologically or cytologically confirmed diagnosis of mUM not amenable to surgical resection.\n- 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 safe serial injections of RP2 and to serial radiographic measurement and that has not been previously treated by surgery, irradiation, ablation, embolization, sclerosis, or any other lesion- directed or regional therapy. Note: Cases in which lesions selected for RP2 injection, and/or as target lesions, are in close proximity to prior lesion-directed therapy region must be discussed with the study Medical Monitor prior to randomization.\n- Must be willing to consent to provide an archival tumor biopsy sample that was collected within 90 days prior to first dose of study intervention (ie, Dose 1) or provide a fresh tumor biopsy during screening or predose on the day of Dose 1. Note: The archival tumor biopsy must be collected after completion of the patient’s most recent prior anticancer therapy.\n- Life expectancy of >3 months as estimated by the Investigator.\n- LDH ≤2 × upper limit of normal (ULN) based on central laboratory testing\n- Has adequate hematologic function based on central laboratory testing, including: •\tWhite blood cell (WBC) count ≥2.0×109/L •\tAbsolute neutrophil count (ANC) ≥1.5×109/L •\tPlatelet count ≥100×109/L •\tHemoglobin ≥8 g/dL (without packed red blood cell [RBC] transfusion within 2 weeks of dosing)\n- Has adequate hepatic function based on central laboratory testing, including: •\tTotal bilirubin ≤1.5×ULN (except patients with known Gilbert Syndrome who must have a total bilirubin of <3.0×ULN) •\tAspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN •\tAlkaline phosphatase (ALP) ≤ 2.5 × ULN\n- Has adequate renal function based on central laboratory testing, defined as serum creatinine ≤1.5×ULN or creatinine clearance ≥30 mL/minute (measured using Cockcroft-Gault formula)."}

Exclusion criteria

• {"criterion_text":"- Occupation of greater than approximately 50% (one-half) of the liver parenchyma by metastatic disease as assessed by the multidisciplinary treating team at the site or by the treating Principal Investigator if a multidisciplinary assessment is unfeasible.\n- Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.\n- Major surgery ≤2 weeks prior to the first dose of study intervention. Note: Patients must have recovered adequately from all acute complications of all previous procedures prior to randomization.\n- Prior malignancy (other than uveal melanoma) active within the previous 3 years, except for locally curable cancers that have apparently been cured, including but not limited to basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.\n- History of significant cardiac disease including myocarditis or congestive heart failure (defined as New York Heart Association Functional Classification III or IV), or unstable angina, serious uncontrolled cardiac arrhythmia, cerebral vascular accident, or myocardial infarction within 6 months of randomization.\n- Has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 480 msec, except in cases of right bundle branch block or when prolongation is caused by implanted pacemaker function.\n- Macroscopic invasion of metastatic disease into a crucial hepatobiliary structure, such as a main portal vein, hepatic artery or vein, or hepatic duct.\n- Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy, based on Investigator assessment.\n- History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition, or disease (with the exceptions of those outlined above) that, in the opinion of the Investigator or the Medical Monitor, would pose a risk to patient safety or interfere with study evaluations, procedures, or compliance.\n- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, and/or make it not in the best interest of the patient to participate, in the opinion of the treating Investigator.\n- Active, known, or suspected autoimmune disease requiring systemic treatment. Note: Patients with type 1 diabetes mellitus, hypothyroidism, or a similar chronic condition requiring only hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or prior autoimmune conditions not expected to recur are eligible.\n- Prior treatment of uveal melanoma metastases with any liver or whole-organ/lobe directed therapies (eg, Hepzato). Note: Patients with history of prior lesion-directed therapies, such as focused radiation therapy, radiofrequency ablation, embolization, surgical resection etc, are eligible for the trial, if at least 1 measurable and injectable tumor is selected and meets Inclusion Criterion 3.\n- History of interstitial lung disease.\n- History of (noninfectious) pneumonitis that required steroids and/or current pneumonitis.\n- Prior treatment with an oncolytic virus.\n- Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).\n- Has received a live vaccine within 28 days prior to the first dose of study intervention. Note: Seasonal influenza vaccines for injection or SARS-CoV-2 are generally inactivated vaccines and are allowed. Live/attenuated vaccines (such as intranasal influenza vaccines) are not allowed. Refer to Section 6.10.1 and Section 6.10.2 for additional guidance.\n- Systemic anticancer therapies within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study intervention. Note: Patients must have recovered (to Grade ≤ 1 or baseline) from all AEs due to previous therapies.\n- Is currently participating in or has participated in a study of an investigational agent(s) within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study intervention.\n- Has received prior radiotherapy within 2 weeks of Dose 1 or has not recovered from side effects of radiotherapy. Note: Patients must have recovered from all radiation-related toxicities (except for radiation-induced xerostomia), not require corticosteroids, and not have had radiation pneumonitis.\n- 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 prior to randomization. Note: Patients who may require a brief course (≤7 days) of corticosteroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded. Physiologic replacement doses of systemic corticosteroids are permitted only if the total daily dose does not exceed >10 mg/day of prednisone equivalent.\n- Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to treatment.\n- Any exposure to immune checkpoint inhibitor (ICIs) and more than one line of systemic therapy since the time of first being diagnosed with metastatic uveal melanoma. Note: •\tFor patients with HLA-A*02:01-positivity, prior treatment with tebentafusp is NOT required for eligibility, provided benefit/risk assessment is deemed favorable by the Investigator. •\tPatients who received an ICI for uveal melanoma in a non-advanced disease setting (for instance, as adjuvant systemic therapy for high-risk disease after treatment with curative intent) are eligible if they had a treatment-free and disease-free interval of at least 6 months. •\tPatients who had previously received ICI for a prior malignancy other than uveal melanoma must be discussed at the start of screening with the Medical Monitor, who will determine eligibility for participation on a case by case basis.\n- Is a person who is deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.\n- Underlying medical conditions that preclude nivolumab and/or ipilimumab use.\n- History of intolerance, allergy, or hypersensitivity to assigned study interventions or components thereof, including components of RP2, if assigned to receive RP2.\n- Extrahepatic involvement of metastatic disease in more than 2 organ systems (not including direct extrahepatic extension in patients with liver metastases).\n- Acute and/or chronic hepatitis B (defined as hepatitis B surface antigen [HbsAg] reactive) and/or acute and/or chronic hepatitis C virus (defined as HCV RNA is detected) based on central laboratory testing. Note: Patients who have been effectively treated are eligible. Patients must be negative for HbsAg and HCV RNA.\n- Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by a competent local health authority or clinically indicated.\n- Uncontrolled infection.\n- Had systemic infection requiring IV antibiotics or other serious active confirmed infection requiring systemic antibacterial, antiviral, and/or antifungal treatment within 14 days prior to Dose 1. Note: Patients who received a short course of prophylactic or presumptive systemic antimicrobial treatment eg, peri-procedurally or for ruled out sepsis will not be excluded.\n- Current active significant herpetic infection(s) and/or prior severe herpetic infections and/or complications of HSV-1 infection (eg, herpetic ocular keratitis and/or encephalitis). Note: Patients with sporadic cold sores may be eligible as long as no active cold sores are present on the day of Dose 1."}

Primary endpoints

• {"endpoint_text":"- OS, defined as the time from randomization to death from any cause","definition_or_measurement_approach":"OS, defined as the time from randomization to death from any cause"}
• {"endpoint_text":"- PFS, defined as the time from randomization to first evidence of disease progression (which is subsequently confirmed) as assessed by BICR per RECIST 1.1 or death from any cause","definition_or_measurement_approach":"PFS, defined as the time from randomization to first evidence of disease progression (which is subsequently confirmed) as assessed by BICR per RECIST 1.1 or death from any cause"}

Secondary endpoints

• {"endpoint_text":"- ORR, defined as the proportion of patients with a confirmed best overall response of CR or PR, as assessed by BICR per RECIST 1.1","definition_or_measurement_approach":"Proportion of patients with a confirmed best overall response of CR or PR, assessed by BICR per RECIST 1.1"}
• {"endpoint_text":"- DOR, defined as the time from onset of response to disease progression (which is subsequently confirmed) or death in patients who achieve either a CR or PR, as assessed by BICR per RECIST 1.1","definition_or_measurement_approach":"Time from onset of response to disease progression (confirmed) or death in patients with CR or PR, assessed by BICR per RECIST 1.1"}
• {"endpoint_text":"- DCR, defined as the proportion of patients with a confirmed best overall response of CR, PR, or Stable Disease (SD), as assessed by BICR per RECIST 1.1","definition_or_measurement_approach":"Proportion of patients with confirmed best overall response of CR, PR, or SD, assessed by BICR per RECIST 1.1"}
• {"endpoint_text":"- CBR, defined as the percentage of patients who achieve a best confirmed response of CR, PR, or SD for at least 24 weeks, as assessed by BICR per RECIST 1.1","definition_or_measurement_approach":"Percentage of patients achieving confirmed CR, PR, or SD for ≥24 weeks, assessed by BICR per RECIST 1.1"}
• {"endpoint_text":"- DOCB, defined as the time from randomization to disease progression or death due to any cause (whichever occurs first) in patients who achieve a best confirmed response of CR, PR, or SD for at least 24 weeks, as assessed by BICR per RECIST 1.1","definition_or_measurement_approach":"Time from randomization to disease progression or death in patients with confirmed CR/PR/SD ≥24 weeks, assessed by BICR per RECIST 1.1"}
• {"endpoint_text":"- Incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) in each study arm","definition_or_measurement_approach":"Incidence and characterization of TEAEs and SAEs collected and reported per study safety reporting procedures in each arm"}
• {"endpoint_text":"- Incidence of imAEs in each study arm","definition_or_measurement_approach":"Incidence of immune-mediated TEAEs (imAEs) collected and compared between arms"}

France

Earliest CTIS Part Ii Submission Date

17-11-2025

Latest Decision Or Authorization Date

12-01-2026

Processing Time Days

56

Number Of Sites

2

Number Of Participants

15

Germany

Earliest CTIS Part Ii Submission Date

19-11-2025

Latest Decision Or Authorization Date

08-01-2026

Processing Time Days

50

Number Of Sites

3

Number Of Participants

29

Italy

Earliest CTIS Part Ii Submission Date

25-11-2025

Latest Decision Or Authorization Date

12-01-2026

Processing Time Days

48

Number Of Sites

3

Number Of Participants

32

Spain

Earliest CTIS Part Ii Submission Date

14-11-2025

Latest Decision Or Authorization Date

23-12-2025

Processing Time Days

39

Number Of Sites

1

Number Of Participants

12

Poland

Earliest CTIS Part Ii Submission Date

11-09-2025

Latest Decision Or Authorization Date

04-01-2026

Processing Time Days

115

Number Of Sites

1

Number Of Participants

10

Primary sponsor

Full Name

Replimune Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States