Clinical Trials

Inclusion Criteria:

• Patients who are 18 years of age or older at the time of signed informed consent.
• Patients with histologically or cytologically confirmed diagnosis of mUM 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 safe serial injections of RP2 and to serial radiographic measurement and that has not been previously treated by operation, irradiation, ablation, embolization, sclerosis, or any other lesion directed or regional therapy.
• 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. Patients must also consent to provide on-treatment biopsies as per protocol. Note: The archival tumor biopsy must be collected after completion of the patient’s most recent prior anticancer therapy.
• Life expectancy of > 6 months as estimated by the Investigator.
• LDH ≤ 2 × upper limit of normal (ULN) based on central laboratory testing.
• 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)
• 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
• 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).
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Female patients of reproductive potential must agree to avoid becoming pregnant and adhere to highly effective contraception requirements during study intervention and for 90 days after last dose of RP2, or 5 months after the last dose nivolumab, or 3 months after the last dose of ipilimumab, whichever occurs last. Note: Patients must agree to follow the manufacturer’s most current prescribing information regarding contraceptive requirements for nivolumab and ipilimumab.
• 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.
• Signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Occupation of greater than 33.3% (one-third) 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.
• Prior treatment of uveal melanoma metastases with any liver or lesion directed therapy, including radiation therapy, radiofrequency ablation, embolization and whole organ (or whole lobe) directed therapies, such as Hepzato Kit. Note: Prior irradiation of bone metastases may be allowed on a case-by-case basis upon discussion with the Sponsor’s Medical Monitor, provided that such treatment has been completed and the patient has fully recovered from any complications or side effects thereof. Note: Prior surgical resection of isolated metastases may be allowed on a case-by-case basis upon discussion with the Sponsor’s Medical Monitor, provided lesions recurrent or remnant at the prior site of resection are not selected for RP2 injection and/or as RECIST target lesions. 
• Any exposure to immune checkpoint inhibitor (ICIs) since the time of first being diagnosed with uveal melanoma. Patients who had previously received immune checkpoint inhibition for a prior malignancy must be discussed at the start of screening with the Medical Monitor, who will determine eligibility for participation on a case-by-case basis.
• Extrahepatic involvement of metastatic disease in more than 2 organ systems (not including direct extrahepatic extension in patients with liver metastases).
• 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. E 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.
• Uncontrolled infection.
• 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.
• 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.
• Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.
• 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.
• 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.
• 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.
• 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.
• Macroscopic invasion of metastatic disease into a crucial hepatobiliary structure, such as a main portal vein, hepatic artery or vein, or hepatic duct.
• Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy, based on Investigator assessment.
• 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.
• 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.
• 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.
• History of interstitial lung disease.
• History of (noninfectious) pneumonitis that required steroids and/or current pneumonitis.
• Prior treatment with an oncolytic virus.
• Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir). 
• 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.  
• Systemic anticancer therapies within 2 weeks of the first dose of study intervention. Note: Patients must have recovered (to Grade ≤ 1 or baseline) from all AEs due to previous therapies. Patients with Grade ≤ 2 neuropathy may be eligible if approved by the Medical Monitor.
• Is currently participating in or has participated in a study of an investigational agent(s) within 4 weeks prior to the first dose (Visit 1). Note: Patients who have entered the follow-up phase of an investigational study may participate only if the first dose (Visit 1) occurs 4 weeks or 5 half-lives (whichever is longer) after the last dose of the previous investigational agent with the longest half-life.
• 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. Patients who have undergone prior radiotherapy may not have received such therapy to organs or anatomic regions containing target lesions and/or lesions selected for RP2 injection. Cases in which lesions selected for RP2 injection, and/or as target lesions, are in close proximity to prior irradiation fields must be discussed with the Sponsor’s Medical Monitor prior to randomization of such patients in the study.
• 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.
• 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.
• Is a person who is deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Underlying medical conditions that preclude nivolumab and/or ipilimumab use.
• History of intolerance, allergy, or hypersensitivity to assigned study interventions or components thereof, including components of RP2, if assigned to receive RP2.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 08/16/2024. Questions regarding updates should be directed to the study team contact.