A study to investigate efficacy of RP2 with nivolumab compared to ipilimumab with nivolumab in adult patients with advanced uveal melanoma not previously treated with immune checkpoint inhibitors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Replimune Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-01-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508784-68-00

ClinicalTrials.gov

NCT06581406

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

• To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on overall survival (OS)
• To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on progression free survival (PFS)

Secondary objectives 7

1. To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on objective response rate (ORR)
2. To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on duration of responses (DOR)
3. To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on disease control rate (DCR)
4. To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on clinical benefit rate (CBR)
5. To compare the effect of RP2 + nivolumab relative to ipilimumab + nivolumab on duration of clinical benefit (DOCB)
6. To characterize the relative safety profiles of patients treated with RP2 + nivolumab to patients treated with ipilimumab + nivolumab
7. To compare the incidence of immune mediated TEAEs (imAEs) in patients treated with RP2 + nivolumab relative to ipilimumab + nivolumab

Conditions and MedDRA coding

metastatic uveal melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patients who are 18 years of age or older at the time of signed informed consent.
2. Patients with histologically or cytologically confirmed diagnosis of mUM not amenable to surgical resection.
3. 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.
4. 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.
5. Life expectancy of >3 months as estimated by the Investigator.
6. LDH ≤2 × upper limit of normal (ULN) based on central laboratory testing
7. Has adequate hematologic function based on central laboratory testing, including: • White blood cell (WBC) count ≥2.0×109/L • Absolute neutrophil count (ANC) ≥1.5×109/L • Platelet count ≥100×109/L • Hemoglobin ≥8 g/dL (without packed red blood cell [RBC] transfusion within 2 weeks of dosing)
8. Has adequate hepatic function based on central laboratory testing, including: • Total bilirubin ≤1.5×ULN (except patients with known Gilbert Syndrome who must have a total bilirubin of <3.0×ULN) • Aspartate aminotransferase (AST) and alanine aminotransferase increased (ALT) ≤3.0×ULN • Alkaline phosphatase (ALP) ≤ 2.5 × ULN
9. 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).
10. 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.
11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
12. 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.
13. 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.
14. Signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 32

1. 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.
2. 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.
3. 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: • For 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. • Patients 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. • Patients 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.
4. Extrahepatic involvement of metastatic disease in more than 2 organ systems (not including direct extrahepatic extension in patients with liver metastases).
5. 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.
6. Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by a competent local health authority or clinically indicated.
7. Uncontrolled infection.
8. 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.
9. 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.
10. Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.
11. 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.
12. 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.
13. 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.
14. 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.
15. Macroscopic invasion of metastatic disease into a crucial hepatobiliary structure, such as a main portal vein, hepatic artery or vein, or hepatic duct.
16. Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy, based on Investigator assessment.
17. 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.
18. 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.
19. 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.
20. History of interstitial lung disease.
21. History of (noninfectious) pneumonitis that required steroids and/or current pneumonitis.
22. Prior treatment with an oncolytic virus.
23. Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Is a person who is deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
31. Underlying medical conditions that preclude nivolumab and/or ipilimumab use.
32. History of intolerance, allergy, or hypersensitivity to assigned study interventions or components thereof, including components of RP2, if assigned to receive RP2.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. OS, defined as the time from randomization to death from any cause
2. 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 7

1. 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
2. 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
3. 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
4. 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
5. 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
6. Incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) in each study arm
7. Incidence of imAEs in each study arm

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Replimune Inc.

Sponsor organisation

Replimune Inc.

Address

500 Unicorn Park Drive Floor Third

City

Woburn

Postcode

01801-3377

Country

United States

Scientific contact point

Organisation

Replimune Inc.

Contact name

Kari Jeschke, SVP Regulatory Affairs

Public contact point

Organisation

Replimune Inc.

Contact name

Kari Jeschke, SVP Regulatory Affairs

Sponsor responsibilities

Article 77 compliance

Replimune Inc.

Contact point sponsor

Replimune Inc.

Article 77 implementation

Replimune Inc.

Locations

5 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 61 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications