A Study to Compare Vusolimogene oderparepvec (VO) Plus Nivolumab With the Doctor's Choice of Treatment in People With Skin Cancer That has Gotten Worse With Other Treatments

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Replimune Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Nov 2025 → ongoing

Decision date (initial)

2025-07-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508612-29-00

ClinicalTrials.gov

NCT06264180

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare survival of the study population treated with VO in combination with nivolumab versus physician’s choice (PC) treatment

Secondary objectives 4

1. To compare the time to progression or death of the study population following treatment with VO in combination with nivolumab versus treatment with PC
2. To compare objective response rate (ORR) of the study population following treatment with VO in combination with nivolumab versus treatment with PC
3. To compare antitumor responses (as per RECIST 1.1), disease stability, and survival rates of the study population following treatment with VO in combination with nivolumab versus PC
4. To compare the safety of treatment with VO in combination with nivolumab versus PC in the study population

Conditions and MedDRA coding

Advanced Melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Male or female who is 12 years of age or older and body weight ≥ 25 kg at the time of signed informed consent.
2. Patients with histologically or cytologically confirmed unresectable or metastatic Stage IIIb through IV/M1a through M1d cutaneous melanoma, as per American Joint Committee on Cancer (AJCC) staging system, 8th edition.
3. Confirmed disease progression (PD) on an anti-PD-1 antibody treatment and an anti-CTLA-4 antibody treatment, administered either as a combination regimen (eg, nivolumab + ipilimumab) or in sequence. a. Treatment with prior anti-PD-1 therapy must have continued for a minimum of 12 weeks Any number of doses of prior anti-CTLA-4 therapy may have been administered in combination with an anti-PD-1. The anti-PD-1-containing therapy must be the immediate prior line of treatment before randomization (for patients with BRAF mutation, see I4). b. Patients who in the physician’s judgement are not candidates for treatment with an anti-CTLA-4 antibody (eg, due to documented clinically significant comorbidities or history of immune-related adverse events) are eligible for the study if they have confirmed PD on an anti-PD-1 antibody (including unresectable disease relapse during adjuvant therapy or <6 months from completion of adjuvant therapy). c. Disease progression must have been confirmed and documented using clinical or radiological assessment by 2 assessments at least 4 weeks apart. Radiological confirmation of PD can occur during the Screening period for this study. Note: If radiographic progression at the initial scan where PD was documented is accompanied by (1) clear clinical progression, defined as a decline in performance status directly attributed to disease or increased disease-related symptoms, so that a situation of pseudo progression can be excluded, OR (2) there is continued growth ≥16 weeks after starting immunotherapy, then radiographic confirmation is not required. Note: For patients with documented PD while on adjuvant therapy with an anti-PD-1 therapy, a confirmatory biopsy can be used in place of a confirmatory scan.
4. Has documented BRAF V600 mutation status or must consent to BRAF V600 mutation testing per local institutional standards during the Screening period. Patients with BRAF mutation should have received prior BRAF-directed therapy (with or without a MEK inhibitor) prior to randomization, unless deemed not clinically indicated at Investigator’s discretion due to concurrent medical condition or prior toxicity. Note: Prior exposure to BRAF-directed therapy (with or without a MEK inhibitor) includes treatment in the adjuvant setting. One line of BRAF-directed therapy (with or without a MEK inhibitor) can be the most recent systemic treatment administered before randomization.
5. Has at least 1 measurable tumor of ≥ 1 cm in longest diameter (or shortest diameter for lymph nodes) and injectable lesion(s) of at least 1 cm in longest diameter.
6. Has adequate hematologic function, including: a. White blood cell count ≥ 2.0 × 109/L b. Absolute neutrophil count ≥ 1.5 × 109/L c. Platelet count ≥ 100 × 109/L d. Hemoglobin ≥ 8 g/dL (without packed red blood cell transfusion within 2 weeks of dosing)
7. Has adequate hepatic function, including: a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN; < 2.0 × ULN for patients with known Gilbert syndrome or liver metastases); b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × ULN (or ≤ 5.0 × ULN, if liver metastases are present); c. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (or ≤ 5.0 × ULN, if liver or bone metastases are present)
8. Has adequate renal function, defined as serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/minute/1.73 m^2 (measured using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).
9. 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. Note: Patients who are on chronic anticoagulant therapy may be randomized if the target INR is ≤ 2.5. For patients requiring deep injection of VO, the INR must be <1.5 at the time of injection.
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1 for patients 18 years and older or a Lansky PS ≥80 for patients 12 to 17 years of age.
11. Life expectancy of at least 3 months.
12. Female and male patients who meet the following criteria: a. Female patients are eligible if not pregnant or breastfeeding and if one of the following applies 1) is a woman of non-childbearing 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 the last dose of RP1, or (b) 5 months after the last dose of nivolumab or Opdualag, or (c) 4 months after the last dose of pembrolizumab, or (d) 6 months after the last dose of dacarbazine, temozolomide, or paclitaxel, whichever is longer. b. Male patients are eligible to participate if they 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 (Appendix A), as a condom may break or leak for at least (a) 90 days after the last dose of RP1 or, (b) 3 months after the last dose of dacarbazine or temozolomide, or (c) 6 months after the last dose paclitaxel, whichever is longer. c. Adolescent male and female patients (12-17 years): Contraceptive and barrier use as well as pregnancy testing is required as appropriate for the age and sexual activity of pediatric participants and as required by local regulations. Note: If the childbearing potential changes after start of the study (eg, a premenarchal female participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who is not heterosexually active becomes active), the participant must discuss this with the investigator, who should determine if a female participant must begin a highly effective method of contraception or a male participant must use a condom. If reproductive status is questionable, additional evaluation should be considered. Note: Patients must agree to follow the manufacturer’s most current prescribing information regarding contraceptive requirements for nivolumab, pembrolizumab, Opdualag, dacarbazine, temozolomide, or paclitaxel. Highly effective methods, barrier guidance, and counseling for adolescents are provided in Appendix A.
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 or β-hCG within 7 days before the first dose of study treatment.
14. Capable of giving signed informed consent as described in Section 10.1.3 which includes willingness to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 27

1. Primary mucosal or uveal melanoma.
2. More than 2 lines of systemic therapy for advanced melanoma. Note: One additional line of systemic therapy in the adjuvant or neoadjuvant setting is allowed if the patient was free of treatment and PD for at least 6 months.
3. Known acute or chronic hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known acute or chronic hepatitis C virus (defined as HCV RNA [qualitative] is detected). Note: Patients who have been effectively treated are eligible for randomization. Patients must be negative for HBsAg and HCV RNA.
4. Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by local health authority or clinically indicated.
5. Active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis) or requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (e.g., acyclovir). Note: Patients with sporadic cold sores may be randomized if no active cold sores are present at the time of first dose of study treatment.
6. Had systemic infection requiring IV antibiotics or other serious active infection requiring antimicrobial, antiviral, or antifungal treatment within 14 days prior to the first dose.
7. Evidence of spinal cord compression or at high risk of spinal cord compression.
8. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis at time of screening. Patients with known central nervous system metastases are eligible if they have received standard-of-care therapy for central nervous system disease (such as stereotactic radiosurgery or radical surgical resection followed by radiotherapy) and have evidence of disease stability on 2 subsequent scans performed at least at a 4-week interval.
9. Serum lactate dehydrogenase (LDH) > 2 × ULN.
10. Major surgery ≤ 2 weeks prior to starting study treatment. Note: Patients must have recovered adequately from all acute complications of all previous procedures prior to randomization.
11. Prior malignancy active within the previous 3 years, except for locally curable cancers that have apparently been cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ (without invasive component) of the prostate, cervix, or breast.
12. 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, myocardial infarction, or significant hypotension within 6 months prior to the first dose of VO.
13. History of life-threatening toxicity related to prior immune therapy except those that are unlikely to recur with standard countermeasures (eg, hormone replacement after adrenal crisis).
14. History or evidence of psychiatric, substance abuse (including IV substance abuse), or any other clinically significant disorder, condition, or disease (with the exception of those described above) that, in the opinion of the Investigator or the Medical Monitor, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion.
15. 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, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
16. Active, known, or suspected autoimmune disease requiring systemic treatment.
17. History of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
18. Prior oncolytic virus therapy or other therapy given by intratumoral administration.
19. Requires chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (e.g., acyclovir).
20. Has received a live vaccine within 28 days prior to the first dose of study treatment.
21. Systemic anticancer therapies within 5 half-lives or 4 weeks of the first dose, whichever is shorter.
22. Is currently participating in or has participated in a study of an investigational agent within 4 weeks prior to the first dose of study treatment.
23. Has received prior radiotherapy within 2 weeks of start of study treatment or has not recovered from radiotherapy.
24. Conditions requiring treatment with immunosuppressive doses (> 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy 14 days before randomization. Note: Patients who require a brief course (≤ 7 days) or 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 dose does not exceed 10 mg/day prednisone equivalent.
25. History of allergy or sensitivity to study drug components (VO, nivolumab, pembrolizumab, relatlimab, dacarbazine, temozolomide, paclitaxel/albumin-bound paclitaxel, dependent on cohort) or prior monoclonal antibody treatment.
26. E 26. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to treatment.
27. Is a person who is deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS)

Secondary endpoints 8

1. Progression-free survival (PFS) (as per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1])
2. ORR (as per RECIST 1.1)
3. Complete response rate (CRR)
4. Duration of response (DOR)
5. Disease control rate (DCR)
6. PFS at 1 and 2 years
7. Survival rates at 1, 2 and 3 years
8. Frequency, nature, and severity of treatment-emergent adverse events (TEAEs), including serious adverse events

Investigational products

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

Test 3

Comparator 5

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

Locations

6 EU/EEA countries · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 140 files

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

Application history

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