CAcTUS - Circulating Tumour DNA Guided Switch

Exclusion Criteria

• •1. Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for unresectable Stage III or Stage IV melanoma.
• •2. Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1 inhibitor is allowed so long as relapse occurred \> 6 months from discontinuation of treatment and treatment not stopped due to grade 3 or 4 toxicity.
• •3. Current use of a prohibited medication
• •4. History of another malignancy. Exception: patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago) or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study.
• •5. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patients safety, obtaining informed consent, or compliance with study procedures.
• •6. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not active) HBV and HCV infection will be permitted).
• •7. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• •8. Patients with active, known or suspected autoimmune disease. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to enrol.
• •9. Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• •10. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• •11. Brain metastases and leptomeningeal metastases are excluded unless:
• •* Asymptomatic and untreated at presentation, OR
• •* Symptomatic lesions have been definitively treated with surgery or stereotactic surgery (whole-brain radiation may be given as adjuvant treatment), and do not require steroids for control of symptoms
• •* Symptomatic metastases, treated or untreated, or metastases requiring steroids to control symptoms, are excluded
• •12. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation
• •13. Coronary syndromes (including myocardial infarction within 6 months or unstable angina)
• •14. A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines with an ejection fraction of \<50%
• •15. Treatment refractory hypertension defined as a blood pressure of systolic\> 150 mmHg and/or diastolic \> 95 mm Hg on \>3 occasions which cannot be controlled by anti-hypertensive therapy;
• •16. Known cardiac metastases;
• •17. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
• •18. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)
• •19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments including monoclonal antibodies, their excipients, and/or dimethyl sulfoxide (DMSO) and/or Polysorbate-80-containing infusions.
• •20. Females who are breast-feeding.
• •21. Prisoners or patients who are involuntarily incarcerated.
• •22. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.