PHOENIX - ECP: Extracorporeal PHotopheresis for immune-related cOlitis and/or hEpatitis in advanced melaNoma with inadequate response to steroId eXposure

Prior treatment

• Positive result for active or previous viral hepatitis B, or active hepatitis C testing at screening.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Previous splenectomy.
• Concurrent treatment with another investigational drug, device, or other investigational intervention.
• Concurrent conditions which may require treatment with high dose corticosteroid (> 1 mg/kg/day) and interfere with the corticosteroid tapering schedule recommended by the protocol.
• Concomitant treatment with any chemotherapy or targeted therapy for the treatment of unresectable or metastatic melanoma.
• Use of any investigational agent within 5 half-lives of the investigational agent prior to randomization.

Other illness

• irAEs in addition to and other than ir-colitis or ir-hepatitis, with a higher severity grade than the irAE for inclusion (ir-colitis/ir-hepatitis) based on ASCO guidelines (see Appendix 1 and Appendix 2).
• Known allergic reaction to any component of 8-methoxsalen, infliximab, vedolizumab, MMF or azathioprine.
• Has aphakia or a history of light sensitive diseases such as lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum, and albinism.
• Hemodynamically unstable, requires vasopressors, and/or has New York Heart Association class III or IV heart failure, uncontrolled hypertension, or ventricular arrhythmias.
• Participants with a history of human immunodeficiency virus or a positive result on human immunodeficiency virus
• Positive result for tuberculosis testing (blood testing).
• Active coronavirus disease 2019 (COVID-19) infection.
• Any active malignancies, other than unresectable or metastatic melanoma.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits poses a significant risk to the participant; or interfere with interpretation of study data.
• Treatment of ir-colitis or ir-hepatitis with any systemic therapy other than corticosteroids.
• Pre-existing liver disease (eg, primary autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis). Isolated low titer autoantibody positivity or mild immunoglobulin G elevation in the setting of hepatic metastases or malignancy-related inflammation, without other evidence of autoimmune hepatitis, will not be considered exclusionary.
• Active alcohol use disorder (per investigator assessment and/or Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria).

Other

• Unable to tolerate the fluid shift associated with the ECP procedure.
• Positive screening test for Epstein-Barr virus (EBV), cytomegalovirus (CMV), or adenovirus.
• Has a diagnosis of uveal melanoma as the sole melanoma subtype (ie, without a diagnosis of cutaneous, acral or mucosal melanoma).
• Inability to operate electronic devices such as a smart phone to complete patient diaries and questionnaires.
• Any known contraindications to study intervention and/or procedures (methoxalen, the ECP procedure, infliximab or vedolizumab, MMF or azathioprine).

• Be adequately informed and understand the nature and risks of the study and must be able to provide a signature and date on the informed consent form (ICF).
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
• Life expectancy > 4 months.
• Has adequate peripheral or central venous access to undergo ECP treatment.
• Participants of non-childbearing potential OR participants using highly effective methods of contraception (see Appendix 4).
• Participants whose sexual partner may become pregnant must use condoms or other methods to ensure effective contraception with partner, and abstain from donating blood, semen, or sperm during the study and for 90 days after the last study treatment (ECP or BAT; see Appendix 4).
• State willingness to comply with all study procedures and availability for the duration of the study.
• Adult (age ≥ 18 years) persons of any sex and gender.
• Diagnosed with unresectable or metastatic melanoma (eg, Stage III and Stage IV).
• Received ICI treatment (eg, anti-PD-1, anti-PD-L1, anti-LAG-3, anti-CTLA-4 antibody, as ICI monotherapy or ICI combination therapy).
• ICI paused or discontinued because of the development of ir-colitis or ir-hepatitis.
• Diagnosed with ir-colitis or ir-hepatitis with a severity of Grade 2 or higher, based on ASCO Guidelines (ir-colitis: diarrhea with an increase of ≥ 4 stools more than at baseline with other potential causes of diarrhea and colitis ruled out by the appropriate evaluations; ir-hepatitis: increase in AST or ALT > 3 × upper limit of normal, total bilirubin > 1.5 × ULN, or alkaline phosphatase > 2.5 × ULN, after exclusion of other potential causes of hepatotoxicity and ruling out the increase is due to development or progression of liver metastases; pre-existing liver metastases are not exclusionary).
• For participant with ir-colitis: Endoscopic evidence of ir-colitis based on colonoscopy, as performed within 10 days prior to randomization.
• Has inadequate response to corticosteroids, defined as: a. No improvement in ir-colitis or ir-hepatitis after at least 72 hours of treatment with systemic corticosteroids (corticosteroid-refractory), OR b. Relapse of ir-colitis or ir-hepatitis (back to Grade 2 or higher) during or after corticosteroid tapering (corticosteroid-dependent).