Evaluation of CD8+ Lymphocyte Infiltration in Metastatic Melanoma Patients Using [89Zr]Zr-Df-IAB22M2C-PET for Early Detection of Immune Checkpoint Inhibitor Side Effects

Trial ID: 2024-512219-37-00
Protocol: CD8-PET
Sponsor: Universitaetsklinikum Tuebingen AöR

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Diseases & Conditions

Malignant melanoma

Objectives

The primary objective of this study is to evaluate the **feasibility** of early detection of immune-mediated side effects in patients with metastatic **melanoma** undergoing immune checkpoint inhibitor therapy. This is achieved through the semiquantitative assessment of **CD8+ lymphocyte** infiltration using noninvasive **[89Zr]Zr-Df-IAB22M2C PET** imaging. The clinical relevance of this objective lies in its potential to enhance the management of immune-related adverse events by enabling timely intervention, thereby improving patient outcomes and optimizing therapeutic strategies in melanoma treatment.

Participants

The clinical trial involves participants diagnosed with **melanoma**, specifically those with metastasized or irresectable forms of the disease. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants are required to be scheduled for immune checkpoint therapy (ICT) as recommended by an interdisciplinary tumor board. The trial does not include a vulnerable population. Participants must adhere to a double-barrier contraception method if applicable, and they should be able to comply with the study visit schedule and other protocol requirements. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the **feasibility** of early detection of immune-mediated side effects in patients with metastatic **melanoma** undergoing immune checkpoint inhibitor therapy. This is achieved through the semiquantitative assessment of CD8+ lymphocyte infiltration using noninvasive [89Zr]Zr-Df-IAB22M2C PET imaging. The trial follows a randomized, double-blind, controlled design and is categorized as a Phase IV study. The estimated duration of the trial is from September 2022 to June 2025, with participant involvement expected to last until 28 days after the last injection of the investigational product.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of metastasized or irresectable melanoma, and ECOG performance status. Following the screening, participants will receive the investigational product via **injection** and will be monitored through follow-up visits to assess the primary endpoint, which is the number of patients for whom the PET imaging was feasible. Secondary endpoints include the detection of grade 3/4 immune-related side effects and the assessment of [89Zr]Zr-Df-IAB22M2C uptake in various tissues.

The end-of-study visit will occur 28 days after the last injection, during which final assessments will be conducted. Participants may be terminated early from the study if they are unable to adhere to the visit schedule, experience severe adverse events, or withdraw consent. The trial aims to provide valuable insights into the early detection of immune-mediated side effects, potentially improving the management of patients undergoing immune checkpoint inhibitor therapy for melanoma.

Treatment

The clinical trial involves the administration of the experimental medication **[89Zr]Zr-Df-IAB22M2C-UKT**, which is an injectable formulation. The active substance in this medication is **zirconium (89Zr) crefmirlimab berdoxam**, a protein-based compound. The medication is administered via injection, with a maximum daily dose of 1.8 mg and a total maximum dose of 3.6 mg over a treatment period of up to 2 days. The primary objective of the trial is to assess the feasibility of early detection of immune-mediated side effects in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy, by evaluating CD8+ lymphocyte infiltration using noninvasive PET imaging with this compound.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration and effects of the experimental medication. Participant compliance with the dosing schedule will be monitored to ensure adherence to the protocol. The trial does not involve any pediatric formulations, and the medication is not classified as an orphan drug. The study is conducted under the authorization of the University Hospital Tuebingen, ensuring adherence to regulatory standards and ethical guidelines.

Efficacy

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the number of patients for whom **[89Zr]Zr-Df-IAB22M2C** PET imaging was feasible. Secondary endpoints include several measures related to the uptake of **[89Zr]Zr-Df-IAB22M2C** as assessed by PET imaging. These include the number of patients affected by grade 3/4 immune checkpoint therapy (ICT) related side effects with detectable differences in PET imaging before and after the first cycle of ICT, and the absolute uptake of **[89Zr]Zr-Df-IAB22M2C** in organs predisposed to immune-related side effects and lymphatic tissue in patients with autoimmune side effects compared to those without. Additionally, the percentage uptake difference of **[89Zr]Zr-Df-IAB22M2C** before and after the first cycle of ICT in these organs and tissues will be evaluated. The trial will also assess the number of patients with detectable differences in **[89Zr]Zr-Df-IAB22M2C** uptake in tumors, metastasis, or lymphatic tissue who show a clinical response to ICT, as well as the absolute and percentage uptake differences in these areas in responders compared to non-responders. These efficacy parameters will be measured using PET imaging, focusing on the semiquantitative assessment of CD8+ lymphocyte infiltration, which is central to the trial's main objective of detecting immune-mediated ICT side effects early.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients ≥18 years of age at the time of signing the informed consent.
Patients with metastasized or irresectable melanoma.
Eastern Cooperative Oncology Group Performance (ECOG) Status ≤2.
Patients scheduled for ICT as recommended by the interdisciplinary tumor board.
Understand and voluntarily sign an informed consent document prior to any study related assessments/ procedures.
Able to adhere to the study visit schedule and other protocol requirements
Consent to practice double-barrier contraception until end of the study (28 days after last [89Zr]Zr-Df-IAB22M2C injection): Females of childbearing potential (FCBP1) and male patients with female partner of childbearing potential1 are willing to use highly effective contraceptive methods at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after end of study treatment after the last dose. Recommendations (CTFG Recommendations related to contraception and pregnancy testing in clinical trials. Version 1.1, 2020) for highly effective contraceptive methods are: a) combined hormonal contraception associated with inhibition of ovulation • oral • intravaginal • transdermal b) progestogen-only hormonal contraception associated with inhibition of ovulation • oral • injectable • implantable c) intrauterine device (IUD) d) intrauterine hormone - releasing system (IUS) e) bilateral tubal occlusion f) vasectomized partner (2) g) sexual abstinence (3) 1For the purpose of this document, a female is considered of childbearing potential (FCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. For the purpose of this document, a man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 2Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. 3In the context of the CTFG guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

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Exclusion Criteria

Known hypersensitivity to [89Zr]Zr-Df-IAB22M2C or its components or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
Persistent toxicity (>Grade 2) according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0, caused by previous cancer therapy, excluding alopecia.
Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0).
Major surgery within 4 weeks of starting study treatment. Patients must have recovered from any effects of major surgery.
Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used.
Heart failure NYHA III/IV.
Patients not able to declare meaningful informed consent on their own.
Women during pregnancy and lactation; female patients of childbearing potential or male patients with female partners of childbearing potential not willing to practice effective contraception by using a double-barrier method from Day 1 until 28 days postdose.
Male patients planning to donate sperm while participating in the study and for at least 28 days after end of study treatment.
Participation in other therapeutic clinical trials or observation period of competing trials.