Immune related adverse events induced by treatment with immune checkpoint inhibitors (monoclocanl antibodies against PD-1, PD-L1 or CTLA-4) MedDRA version: 21.1 Level: LLT Classification code 10043408 Term: Therapeutic agent toxicity System Organ Class: 10022117 - Injury, poisoning and procedural complications MedDRA version: 26.1 Level: LLT Classification code 10067033 Term: Drug side effect System Organ Class: 10018065 - General disorders and administration site conditions MedDRA version: 2
Conditions
Interventions
Trade Name: UVADEX
Product Name: UVADEX
Pharmaceutical Form: Sterile concentrate
INN or Proposed INN: Methoxsalen
CAS Number: 298-81-7
Other descriptive name: METHOXSALEN
Concentration unit: mg/ml mil
Sponsors
Medical Center - University of Freiburg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female patients aged =18 years with adequate German written and oral language skills 2. 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. 3. 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. 30% of the patients that will be included should have non-skin cancer. • Patients should have clinical and/or histological evidence of immune-related adverse events as follows: o Colitis ? Diarrhea with increase of =4 stools over baseline ? No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent o o Hepatitis ? Alanine aminotransferase and/or aspartate aminotransferase =3x ULN if baseline was normal; or =3x baseline if baseline was abnormal and/or total bilirubin >1.5 ULN. ? No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent o Pneumonitis ? Radiographic changes that involve more than one lobe of the lung or =25% of lung parenchyma and new symptoms such as cough, dyspnea or chest painor new oxygen therapy ? No improvement after 72h treatment with 1 mg/kg BW/day prednisolone equivalent o Dermatitis ? Skin erythema, maculopapular or pustulopapular rRash covering >=30% of the body surface area and moderate or severe symptoms ? No improvement after 72h treatment with at least 1 mg/kg BW/day prednisolone equivalent 4. Maximum of one additional (second line) therapy after Steroid treatment before ECP starts (e.g. infliximab for colitis) 5. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 1 week prior to the start of study drug. Males who are sexually active with WOCBP must use during the duration of the study and up to 5 months afterwards a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy (see also 10.9). Patients must abstain from donating blood, semen, or sperm during participation in the study 6. Women must not be breastfeeding. 7. ECOG performance status 0, 1, or 2 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 8 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 6
Exclusion criteria
Exclusion criteria: 1. 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. 2. Positive result for HIV. 3. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic 4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 5. Patients who require vasopressors, and/or have NYHA class III or IV heart failure. 6. Uncontrolled hypertension or ventricular arrhythmias. 7. 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. 8. 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 9. Known allergies, hypersensitivity, or intolerance of methoxypsoralen, excipients, or similar compounds, acid-citrate-dextrose or similar compounds 10. Aphakia 11. Sexually active men and 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 last ECP procedure (see also 10.9 12. Inability to tolerate extracorporeal volume loss 13. Previous splenectomy 14. Pregnancy and lactation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Our preliminary data demonstrate that irAEs induced by immune checkpoint blockade can be successfully treated with ECP (Apostolova et al. NEJM 2020). We therefore intend to launch a clinical phase 1/2 trial to validate this finding in a prospective trial. The primary objective is evaluation of safety of ECP treatment in patients with irAEs. ;Secondary Objective: •As a secondary objective, we will determine the efficacy of ECP as a treatment for immune-related adverse events and its effect on tumor progression. •To evaluate the investigator-assessed objective response rate (ORR) to treatment after 6 and 12 weeks of ECP therapy The response criteria for each organ are described in chapter 6.2. •To assess time to response •To assess the duration of investigator-assessed clinical response •To assess overall survival (OS) at 1 year after end of ECP treatment •To measure the time to complete discontinuation of other immunosuppressive therapy •To assess changes in immune cell phenotype and metabolism during treatment •To assess the relapse rates of irAEs upon discontinuation of ECP and rechallenge with an immune checkpoint inhibitor •To assess the incidence of tumor progression or relapse;Primary end point(s): To evaluate the rate of treatment-related adverse events (AEs) and serious adverse events (SAEs) in patients treated with ECP for immune-checkpoint inhibitor-induced colitis, pneumonitis, hepatitis or dermatitis. A positive result from the study is defined as =50% of the patients developing a treatment-related SAE.;Timepoint(s) of evaluation of this end point: Adverse events and serious adverse events will be registered and reported according to the guideline of ICH/GCP. Rates of adverse events and of serious adverse events will be calculated with corresponding 95% confidence intervals. efficacy analyses will be based on the full analysis set and will be considered as descriptive results. Interim safety analysis: After the first 14 patients have co | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoints: • To evaluate the investigator-assessed objective response rate (ORR) to treatment after 6 and 12 weeks of ECP therapy The response criteria for each organ are described in chapter 6.2. • To assess time to response • To assess the duration of investigator-assessed clinical response • To assess overall survival (OS) at 1 year after end of ECP treatment • To measure the time to complete discontinuation of other immunosuppressive therapy • To assess changes in immune cell phenotype and metabolism during treatment • To assess the relapse rates of irAEs upon discontinuation of ECP and rechallenge with an immune checkpoint inhibitor • To assess the incidence of tumor progression or relapse ;Timepoint(s) of evaluation of this end point: Secondary endpoints: Descriptive analyses of the secondary endpoints will be performed. OS probabilities will be estimated and displayed using the Kaplan Meier method. The analysis of secondary time-to-event endpoints with competing risks will be performed by means of the Aalen Johanson estimator for the calculation of cumulative incidence rates. As this is a phase 1/2 trial without the intention of a confirmatory proof of efficacy, no formal sample size calculation is performed. The initial determination to include 14 evaluable patients is mainly based on feasibility considerations. It is expected that only few SAEs will occur. If the probability of any ECP-related SAE for a patient is 20% (p=0.2), the probability to observe at least one patient with a treatment-related SAE is 0.897. | — |
Countries
Germany
Contacts
Public ContactDepartment for Medicine I
Medical Center - University of Freiburg
Outcome results
None listed