Testing bifikafusp alfa, onfekafusp alfa, and pembrolizumab combination in patients with advanced melanoma that did not respond to previous immunotherapy

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What is this study about?

This study involves patients with melanoma, a type of skin cancer that has spread and cannot be removed by surgery. The study focuses on people whose cancer has continued to grow despite previous treatment with drugs that work by helping the immune system fight cancer. The study will test three different treatment combinations, all using a drug called pembrolizumab given through a vein, along with one or two experimental medicines injected directly into the tumors. These experimental medicines are called Darleukin (also known as L19IL2) and Fibromun (also known as L19TNF). Patients will receive either Darleukin alone, Fibromun alone, or both Darleukin and Fibromun together, all combined with pembrolizumab. The purpose of this study is to see if these treatment combinations can help shrink or control the cancer in patients whose disease has gotten worse while taking similar immune system drugs.

During the study, patients will be assigned to one of the three treatment groups. They will receive pembrolizumab through a vein every three weeks, while the experimental medicines will be injected directly into accessible tumors on the skin or under the skin every four weeks. Treatment will continue for up to two years or until the cancer gets worse, side effects become too severe, or the patient or doctor decides to stop. Throughout the study, doctors will check how the tumors respond to treatment using scans and physical examinations. Patients will also have blood tests and other assessments to monitor their health and any side effects from the treatment.

To participate in this study, patients must have melanoma at an advanced stage with tumors that can be injected with the experimental medicines. They must have previously received treatment with drugs that block a protein called PD-1 or PD-L1, and their cancer must have either not responded to this treatment or started growing again during or shortly after such treatment. Patients with certain genetic changes in their cancer called BRAF mutations should have already tried or declined specific targeted treatments before receiving the PD-1 blocking drugs. The study requires that patients have recovered from any severe side effects from their previous treatments and have adequate organ function to safely receive the study medications.

1 Initial treatment preparation

Before starting the treatment, a biopsy will be taken from a lymph node for laboratory analysis. This can be either a stored sample from a previous procedure or a newly obtained sample.

Blood samples will be collected within 14 days before treatment starts to check that organs are functioning properly.

Test results confirming negative status for HIV (human immunodeficiency virus), HBV (hepatitis B virus), and HCV (hepatitis C virus) must be documented. For hepatitis B, specific markers will be checked, and if previous exposure is documented, an additional blood test for HBV-DNA will be required.

Any side effects from previous treatments must have decreased to mild levels or returned to baseline. Exceptions may apply for certain conditions such as hair loss, skin pigment changes, mild nerve problems, or hormone-related side effects that are being managed.

At least 4 weeks must have passed since the last treatment for any side effects from previous immunotherapy, and these effects must be fully resolved.

2 Combined treatment phase

Treatment will consist of two types of medication given together: one administered directly into the tumor and another given through a vein.

The medication given through the vein is pembrolizumab (also known as Keytruda), which will be administered as an intravenous infusion (slowly delivered into a vein over a period of time).

The medication injected directly into the tumor will be one of the following, depending on the assigned treatment group: bifikafusp alfa (also known as Darleukin) or onfekafusp alfa (also known as Fibromun), or a combination of both. These are administered as intralesional injections (injected directly into the tumor tissue).

The injections into the tumor will target at least one melanoma lesion that is accessible for injection, measuring at least 5 millimeters in diameter, or multiple smaller lesions that together measure at least 5 millimeters.

This combined treatment approach will continue for up to 2 years from the first injection into the tumor.

3 Monitoring and assessments

Regular visits will be scheduled to monitor response to treatment and check for any side effects.

Disease status will be assessed according to RECIST v1.1 criteria, which is a standardized method for measuring tumor size and determining whether the cancer is responding to treatment, staying stable, or progressing.

An additional biopsy may be requested at week 18 of treatment for further laboratory analysis.

If the disease progresses during treatment, another biopsy may be requested at the time treatment is stopped.

4 Follow-up period

After the last dose of study treatment, follow-up will continue to monitor long-term outcomes.

If applicable, contraception must be continued for at least 120 days after the last dose of treatment.

Male patients must use two methods of contraception simultaneously (spermicidal gel plus condom) and refrain from sperm donation from the start of treatment until three months after the last dose.

A pregnancy test will be performed at the safety follow-up visit for women of childbearing potential.

Who Can Join the Study?

You must be over 18 years of age when you sign the consent form
You must have a confirmed diagnosis of melanoma (a type of skin cancer) that cannot be removed by surgery and has spread to other parts of the body at stage III B, C, D or stage IV
You must have melanoma that has not responded to or has grown despite treatment with anti-PD1 therapy (a type of cancer treatment that helps your immune system fight cancer)
You must have received at least 2 doses of anti-PD1 treatment before your cancer started growing again
Your cancer must have grown within 12 weeks after your last dose of anti-PD1 treatment
If you have a BRAF mutation (a specific change in your cancer cells), you must have received or declined treatment with BRAF and MEK inhibitors (specific cancer medicines) and then received anti-PD1 therapy that did not work
You must have at least one tumor that can be injected directly, located in the skin or under the skin or in a lymph node, measuring at least 5 millimeters
You must have tumors that can be measured to track if treatment is working
You must be able to provide a tissue sample from a tumor biopsy, either from a previous biopsy or a new one
You must have an ECOG performance status of 0 to 1, which means you are able to carry out normal activities or have only light restrictions
Your organs (such as liver, kidneys, and bone marrow) must be working well enough, as shown by blood tests done within 14 days before starting treatment
You must test negative for HIV (a virus that affects the immune system), hepatitis B, and hepatitis C (viruses that affect the liver)
Any side effects from previous cancer treatments must have improved to mild levels or gone away completely, except for hair loss
Any side effects from previous immune checkpoint therapy must be fully resolved, and you must not have needed treatment for these side effects for at least 4 weeks before joining the study
You must not have had severe immune-related side effects from previous checkpoint therapy
If you are a woman who can become pregnant, you must not be pregnant or breastfeeding, and you must agree to use highly effective birth control during treatment and for at least 120 days after the last dose
If you are a man with a female partner who can become pregnant, you must agree to use two methods of birth control at the same time from the start of the study until three months after the last dose, and you must not donate sperm during this time
You must be willing and able to attend all scheduled visits, follow the treatment plan, and complete required tests

Who Cannot Join the Study?

You have brain metastases (cancer that has spread to the brain) that are causing symptoms or that you recently received treatment for
You have cancer that has spread to the leptomeninges (thin membranes covering the brain and spinal cord)
You have uveal melanoma (a type of melanoma that starts in the eye)
You have active infections that affect your whole body, including infections caused by the human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
You have diseases where your immune system (the body’s defense system) attacks your own body
You are taking medicines that suppress your immune system, such as corticosteroids (anti-inflammatory drugs) in high doses
You have serious heart problems, including heart failure (when the heart cannot pump blood properly), coronary artery disease (blocked blood vessels in the heart), or irregular heartbeats that are not well controlled
You have severe lung disease or breathing problems
You have severe liver disease
You have severe kidney disease
You have had a different type of cancer within the last 2 years, except for certain skin cancers or early-stage cancers that have been completely removed
You are pregnant or breastfeeding
You have had severe allergic reactions to similar medicines in the past
You have received other experimental treatments within a certain time period before joining this study
You have any medical condition that the doctor believes would make it unsafe for you to participate in the study

Where you can join this trial?

Verified and Recommended Sites

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Verified Sites

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Other Sites

Site Name	City	Country
IRCCS Istituto Nazionale Tumori Fondazione Pascale	Naples	Italy
Universitaetsklinikum Schleswig-Holstein AöR	Kiel	Germany
Universitaetsklinikum Tuebingen AöR	Tuebingen	Germany
Medical Center – University Of Freiburg	Freiburg Im Breisgau	Germany

Trial status

Country	Status	Recruitment Start
Germany	Recruiting	12.01.2026
Italy	Not yet recruiting	12.01.2026

Trial locations

Investigated drugs:

L19IL2 is an experimental medication that combines a targeted antibody with a substance called interleukin-2. It is injected directly into tumors to help activate the immune system to fight cancer cells at the tumor site.

L19TNF is an experimental medication that combines a targeted antibody with a substance called tumor necrosis factor. It is injected directly into tumors to help destroy cancer cells and activate the immune system against the tumor.

Pembrolizumab is an immunotherapy medication given through the bloodstream that helps the immune system recognize and attack cancer cells throughout the body. It works by blocking a protein that prevents immune cells from fighting cancer.

Investigated diseases:

Skin cancer

Metastatic Melanoma – Metastatic melanoma is an advanced form of skin cancer that has spread beyond its original location to other parts of the body. It develops when melanocytes, the cells that produce skin pigment, grow uncontrollably and invade distant organs or tissues. In clinical stage III, the cancer has spread to nearby lymph nodes or skin areas, while stage IV indicates spread to distant organs such as the lungs, liver, or brain. The disease progresses when melanoma cells break away from the primary tumor and travel through the bloodstream or lymphatic system to establish new tumors in other body parts. Unresectable melanoma means the cancer cannot be completely removed through surgery due to its location, size, or extent of spread. Some patients develop resistance to certain treatments, meaning the cancer continues to grow despite therapy.

Trial ID:

2024-519326-20-00

Protocol code:

PH-ICKPD1-02/21

NCT ID:

NCT06284590

Trial Phase:

Therapeutic exploratory (Phase II)

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Testing bifikafusp alfa, onfekafusp alfa, and pembrolizumab combination in patients with advanced melanoma that did not respond to previous immunotherapy

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?