VO and Nivolumab vs Physician's Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs [IGNYTE-3]

Exclusion Criteria28

• E 1. Primary mucosal or uveal melanoma. E 2. More than 2 lines of systemic therapy for advanced melanoma. Note: One additional line of anti-PD-1 therapy in the adjuvant or neoadjuvant setting is allowed if the patient was free of treatment and of PD for at least 6 months and subsequently had confirmed PD on an anti-PD-1 and an anti-CTLA-4 antibody therapy administered in the advanced setting.
• E 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.
• E 4. Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by local health authority or clinically indicated.
• E 5. Active significant herpetic infections or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis) or requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, 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.
• E 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.
• E 7. Evidence of spinal cord compression or at high risk of spinal cord compression.
• E 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.
• E 9. Serum lactate dehydrogenase (LDH) \> 2 × ULN. E 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.
• E 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.
• E 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, or myocardial infarction within 6 months from first dose of VO.
• E 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).
• E 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.
• E 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.
• E 16. Active, known, or suspected autoimmune disease requiring systemic treatment.
• E 17. History of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
• E 18. Prior oncolytic virus therapy or other therapy given by intratumoral administration.
• E 19. Requires chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).
• E 20. Has received a live vaccine within 28 days prior to the first dose of study treatment.
• E 21. Systemic anticancer therapies within 5 half-lives or 4 weeks of the first dose, whichever is shorter.
• E 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.
• E 23. Has received prior radiotherapy within 2 weeks of start of study treatment or has not recovered from radiotherapy.
• E 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.
• E 25. History of allergy or sensitivity to study drug components (VO, nivolumab, pembrolizumab, or relatlimab) or to cisplatin or carboplatin or paclitaxel (dependent on cohort) or prior monoclonal antibody treatment.
• E 26. 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.
• E 27. Is a person who is deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.