ECP for Immune-related Adverse Events After Checkpoint Inhibitor Treatment

Immune checkpoint inhibitors (ICI) have improved the long-term survival of patients with metastatic tumors. However, approximately 50% of the patients treated with ICI develop serious immune-related adverse events (irAE). A recent study reported that grade 3 or higher irAE occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 patients (33.3%) who received nivolumab alone. Other studies report an overall frequency of grade 3-5 irAE in 24% - 59% of patients treated with nivolumab 1 mg/kg body weight and ipilimumab 3 mg/kg body weight. An incidence of 33.3% was reported when patients were treated with nivolumab 3 mg/kg body weight and ipilimumab 1 mg/kg body weight. The most common events reported during combined ICI treatment are diarrhea, rash, pruritus, hepatitis, hypothyroidism, neurological disease and pneumonitis. These numbers show that irAE are a particularly frequent complication of ICI and limit their use.

This retrospective analysis is launched to validate the finding made with the individual patient in a larger patient cohort. The analysis will include the evaluation of safety of ECP treatment in patients with irAEs and collect data on the efficacy of ECP as a treatment for immune-related adverse events and its effect on tumor progression.

Inclusion criteria

• Male and female patients aged ≥18 years
• Written informed consent:

• Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines.
• Subjects must be able to understand and willing to comply with scheduled visits, treatment schedule, laboratory tests and mandatory collection of blood, and other requirements of the study.
• Subject Re-enrollment: This trial permits the re-enrollment of a subject that has discontinued the study as a screening failure. If re-enrolled, the subject must be re-consented.
• Target population

• Patients who have received treatment with an anti-PD-1, anti-PD-L1 or an anti-CTLA-4 antibody or any combination of these for any type of malignancy in the last 24 months before screening.
• Patients should have clinical and/or histological evidence of immune-related adverse events as follows:

• Colitis Diarrhea with increase of ≥4 stools over baseline No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent
• Hepatitis Alanine aminotransferase and/or aspartate aminotransferase ≥3x ULN if baseline was normal; or ≥3x baseline if baseline was abnormal No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent
• Pneumonitis Radiographic changes and new symptoms such as cough, dyspnea or chest pain No improvement after 72h treatment with 1 mg/kg BW/day prednisolone equivalent Dermatitis Skin erythema, maculopapular or pustulopapular rash covering ≥30% of the body surface area No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent
• Maximum of one additional (second line) therapy after Steroid treatment before ECP starts (e.g. infliximab for colitis)
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 1 week prior to the start of study drug.
• Women must not be breastfeeding.
• ECOG performance status 0, 1, or 2

Exclusion criteria

• Active treatment in a clinical study of any investigational agent within 14 days prior day 0 or within 5 half-lives of the study treatment, whichever is greater.
• Positive result for HIV.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Mechanical ventilation or patients who have resting O2 saturation <90% by pulse-oximetry.
• Patients who require vasopressors, and/or have NYHA class III or IV heart failure.
• Uncontrolled hypertension or ventricular arrhythmias.
• Previous or concurrent malignancies within the last 3 years of enrollment other than the disease for which checkpoint-inhibitor blockade was applied. Exceptions are adequately treated basal or squamous cell skin cancer, or any other cancer from which the subject has been disease-free for more than 3 years.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data
• Known allergies, hypersensitivity, or intolerance of methoxypsoralen, excipients, or similar compounds, heparin or similar compounds
• Aphakia
• Female patients of child-bearing potential who are not willing to use highly effective methods of contraception during the trial and at least 5 months after the ECP procedure (see also 10.9)
• Inability to tolerate extracorporeal volume loss
• Previous splenectomy
• Pregnancy and lactation