Evaluation of Adoptive TIL Therapy Combined with Low-Dose Peginterferon Alfa-2a and Nivolumab in Patients with Metastatic Melanoma
- Trial ID
- 2024-516125-31-02
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and toxicity of the first Tumor-Infiltrating Lymphocytes (TIL) and nivolumab, followed by the combination of TIL, PEG-Interferon Alfa-2a (PEG-IFNa), and nivolumab, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This is clinically relevant as it aims to ensure the therapeutic regimen's safety profile in patients with metastatic melanoma, potentially improving treatment outcomes and patient management.
Secondary objectives include:
- Evaluating the disease control rate according to RECIST 1.1 criteria and immune-related response criteria (irRC), overall survival (OS), progression-free survival (PFS), and quality of life. Disease control is defined as Stable Disease (SD), Partial Response (PR), or Complete Response (CR).
- Establishing a possible prognostic biomarker profile.
- Identifying potential differences between patients with a clinical response and those with past responses to immunotherapy through immunomonitoring of the infusion T cell product.
- Analyzing potential correlations between clinical response and hypothesis-related immune parameters.
- Studying differences in immunological characteristics between CD8-rich and CD8-poor metastases within a patient detected using CD8-immunoPET/CT, including differences between TIL derived from both locations.
- Describing the clinical response to Adoptive Cell Therapy (ACT) in relation to [89Zr]Zr-crefmirlimab berdoxam uptake on a lesion level.
- Investigating if [89Zr]Zr-crefmirlimab berdoxam uptake in non-affected tissues is related to immune-related adverse events caused by ACT.
- Studying potential working mechanisms of the different treatment compounds in Peripheral Blood Mononuclear Cells (PBMCs) of the patients.
Participants
The clinical trial focuses on individuals diagnosed with **metastatic melanoma**, specifically targeting those with unresectable regional metastatic melanoma or stage IV melanoma. The study population includes both male and female participants aged 18 years and older. Participants are required to have a histologically or cytologically confirmed diagnosis of metastatic skin melanoma and must have experienced disease progression following prior treatments, such as BRAF-inhibitors, MEK-inhibitors, or immunotherapy, including anti-PD1 treatment. The trial excludes vulnerable populations and requires participants to have a WHO performance status of 0 or 1, indicating a relatively stable general health status. Key lifestyle considerations include the requirement for neurologically stable patients with brain metastases and the absence of certain viral infections. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **toxicity** of a combination therapy involving Tumor-Infiltrating Lymphocytes (TIL), nivolumab, and PEG-interferon alfa-2a in patients with **metastatic melanoma**. This is a single-center, phase I/II trial, which is not classified as low intervention. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from May 7, 2018, to December 31, 2027, allowing for comprehensive data collection and analysis over an extended period.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, disease progression, and previous treatment history. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to evaluate any adverse effects according to the CTCAE 4.0 criteria. The primary endpoint focuses on the safety and toxicity of the treatment regimen, while secondary endpoints include disease control rate, overall survival, progression-free survival, and quality of life assessments. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any long-term effects observed.
The expected length of participant involvement is contingent upon their response to the treatment and the absence of severe adverse events. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, withdrawal of consent, or any medical condition that contraindicates continued participation. Participants are required to meet specific laboratory and clinical criteria throughout the study to ensure their safety and the integrity of the trial data.
Treatment
The clinical trial involves the administration of **Zirconium Zr 89 crefmirlimab berdoxam**, an experimental medication provided in the form of an **injection/infusion**. This compound is a protein-based substance, specifically a minibody against CD8 conjugated to desferrioxamine and labeled with zirconium Zr 89. The administration route is **intravenous**, and the frequency of administration is determined by the study protocol. The medication is developed by IMAGINAB, INC., and is not a pediatric formulation. Participant compliance with the dosing schedule is monitored throughout the trial.
Another experimental treatment in the study is **TIL cells**, which are administered via **infusion**. These cells are a structurally diverse substance used in cell therapy, provided by Leiden University Medical Center. The route of administration is **intravenous**, and the dosing schedule is specified in the trial protocol. TIL cells are not formulated for pediatric use, and adherence to the treatment regimen is closely monitored.
The trial also includes the use of **Peginterferon alfa-2a**, which serves as an auxiliary treatment. This protein-based medication is administered through **injection**. The pharmaceutical form is denoted as PHF00231MIG, and it is not intended for pediatric patients. The administration schedule and dosage are outlined in the study protocol, with compliance being tracked to ensure adherence to the treatment plan.
In addition to the experimental treatments, the study may involve standard-of-care therapies or comparator treatments as per the trial design. The administration of these treatments is conducted according to established medical guidelines and is monitored for participant compliance. The trial aims to evaluate the safety and toxicity of the combination of TIL cells, Peginterferon alfa-2a, and other investigational agents in the context of metastatic melanoma.
Efficacy
Efficacy in the clinical trial titled "(ACTME) Adoptive TIL therapy with low-dose PEG-IFNa plus nivolumab in metastatic melanoma" will be assessed through several secondary endpoints. These include the evaluation of the disease control rate, which will be assessed by physical examination and imaging studies such as CT and/or MRI. The assessments will be conducted according to RECIST 1.1 and immune-related response criteria (irRC). Additionally, overall survival (OS) and progression-free survival (PFS) will be evaluated. Immune-related parameters will also be analyzed to provide further insights into the treatment's efficacy. Quality of life is measured by the DMTR and will be assessed as part of the trial's comprehensive evaluation of efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- Histologically or cytologically proven metastatic skin melanoma
- Melanoma must be at one of the following AJCC 2009 stages: - Unresectable (or residual) regional metastatic melanoma, i.e. in terms of AJCC 2009 classification unresectable stage III melanoma, or- Stage IV melanoma, i.e. distant metastatic disease (any T, any N, M1a, M1b or M1c), and normal LDH - Patients have failed on standard treatment options
- Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
- Presence of measurable progressive disease according to RECIST version 1.1
- Expected survival of at least 3 months
- WHO performance status ≤1
- Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified: Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/μl Lymphocytes ≥ 700/μl Platelets ≥ 100,000/μl Creatinine clearance ≥ 60 min/ml Serum bilirubin ≤ 40 μmol/l ASAT and ALAT ≤ 5 x the normal upper limit LDH ≤ 2 x the normal upper limit
- Viral tests must be performed at least 30 days before surgery: - Negative for HIV type 1/2, HTLV and TPHA - No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum - No antibodies against HCV (hepatitis C virus) in the serum
- Able and willing to give valid written informed consent
- Progressive disease on prior treatment with f.e. BRAF-inhibitors, MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy with BRAF-/MEK-inhibitors must have been discontinued for at least two weeks before start of study treatment. Treatment with immunotherapy must have been discontinued for at least four weeks before start of study treatment.
Exclusion Criteria
- Patients with brain metastases who are neurologically unstable and/or use dexamethasone
- Pregnancy or breastfeeding
- Known allergy to penicillin or streptomycin (used during the culturing of T cells)
- Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or otherconditions requiring concurrent medications not allowed during this study
- Clinically significant heart disease (NYHA Class III or IV)
- Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
- Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma.
- Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the associated with the participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
- Lack of availability for follow-up assessments
- Subjects with a condition requiring systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) orany immunosuppressive therapy within 14 days prior to planned date for first dose of study treatment. Topical,inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 07 May 2018 | — |
| Netherlands | — | — | 58 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PEGINTERFERON ALFA-2A | Test | PHF00231MIG | INJECTION | — | — | SCP187427 |
TIL cells | Test | INFUSION | INTRAVENOUS | — | — | PRD11635836 |
Zirconium Zr 89 crefmirlimab berdoxam | Other | INJECTION/INFUSION | INTRAVENOUS | — | — | PRD11648692 |