L19IL2/L19TNF + Pembrolizumab for Melanoma

(INTACT/MeRCI Trial)

Overseen By Marco Taras

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Philogen S.p.A.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: More than 10 lesions, Uveal melanoma, Active autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

162 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new methods for treating advanced melanoma, a type of skin cancer that cannot be removed by surgery and has stopped responding to standard treatments. It examines three different treatment combinations involving L19IL2 (a component of the experimental treatment Daromun), L19TNF (also known as Fibromun), and pembrolizumab. Individuals with melanoma that persists despite previous anti-PD1 therapy and who have at least one treatable melanoma lesion may be suitable candidates. The trial aims to determine if these new therapies outperform the current approach. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like systemic anti-cancer therapy or immunosuppressive therapy, you may need to stop them before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that L19IL2 and L19TNF, whether used together or separately, are generally safe in other conditions. For instance, in hard-to-treat non-melanoma skin cancer, patients tolerated these treatments well, experiencing no significant side effects. This suggests these therapies are usually safe.

In studies involving injectable melanoma lesions, patients also tolerated the treatment well, with no major safety issues reported. This indicates that L19IL2 and L19TNF are typically well-tolerated in humans.

When combined with pembrolizumab, a drug already approved for melanoma, the safety results remain positive. Pembrolizumab is widely used, and its safety is well-known. This background provides extra reassurance about the safety of these treatment combinations in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving L19IL2, L19TNF, and pembrolizumab for melanoma because they offer a unique approach compared to standard options like targeted therapies and immunotherapies such as ipilimumab and nivolumab. Unlike most treatments that focus solely on systemic administration, L19IL2 and L19TNF are delivered directly into the tumor (intralesional), potentially enhancing the immune response right where it's needed most. These treatments also leverage innovative fusion proteins (L19IL2 and L19TNF), which combine tumor-targeting antibodies with powerful cytokines, potentially increasing their effectiveness and specificity. This targeted approach may lead to better outcomes with fewer side effects, making it a promising option in the fight against melanoma.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that L19IL2 and L19TNF, when combined with pembrolizumab, offer promising treatments for melanoma. In this trial, participants will receive one of the following combinations: systemic pembrolizumab with intralesional L19IL2, systemic pembrolizumab with intralesional L19TNF, or systemic pembrolizumab with both intralesional L19IL2 and L19TNF. These drugs help the immune system identify and attack cancer cells, potentially slowing tumor growth. Earlier studies demonstrated that L19IL2 and L19TNF effectively treat difficult cancers and help prevent recurrence or spread in melanoma patients. These treatments are also considered safe, warranting further exploration. The goal of combining these treatments is to achieve better results than current anti-PD1 therapies alone. ^{1 2 5 6 7}

Who Is on the Research Team?

Danielle Bello

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for people with advanced melanoma that can't be surgically removed and who haven't responded to previous anti-PD1 therapy. Participants should have a certain level of physical health, no autoimmune diseases, and not be receiving other cancer treatments.

Inclusion Criteria

Participants must have documented negative test for HIV, HBV and HCV

I am using approved birth control methods if I can become pregnant.

Participant provides written informed consent for the trial

Exclusion Criteria

Participants with specific diagnostic assessments

Participants with certain medical conditions

I have active brain metastases or carcinomatous meningitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Treatment

Participants receive intralesional L19IL2, L19TNF, or L19IL2/L19TNF in combination with systemic pembrolizumab

4 weeks

Pembrolizumab administered every 3 weeks

Follow-up

Participants are monitored for progression-free survival and overall survival

Up to 3 years

Safety Run-in

Safety evaluation of the first 12 patients in each arm for treatment-related adverse events

21 days

What Are the Treatments Tested in This Trial?

Interventions

• L19IL2
• L19TNF
• Pembrolizumab

Trial Overview The study tests the effectiveness of L19IL2 alone, L19TNF alone, and their combination with Pembrolizumab (KEYTRUDA®), compared to previous standard treatment in patients whose melanoma didn't respond to initial anti-PD1 therapy.

How Is the Trial Designed?

Group I: Systemic pembrolizumab in combination with intralesional L19TNF (Arm 2) Experimental Treatment 2 Interventions

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19TNF, and will continue every 3 weeks for approximately 2 years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity, whichever comes first.

Group II: Systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3) Experimental Treatment 2 Interventions

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19IL2/L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19IL2/L19TNF, and will continue every 3 weeks for approximately 2 years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity, whichever comes first.

Group III: Systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1) Experimental Treatment 2 Interventions

Two-weeks screening period and a 4-weeks open-label intralesional treatment period with L19IL2. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with L19IL2, and will continue every 3 weeks for approximately 2 years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity, whichever comes first.

Who Is Running the Clinical Trial?

Philogen S.p.A.

Lead Sponsor

Trials

42

Recruited

2,400+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Pembrolizumab (Keytruda) is an effective treatment for advanced melanoma, showing significant improvements in progression-free survival and overall response rates compared to ipilimumab and chemotherapy in clinical trials involving patients with varying treatment histories.

The drug has a manageable safety profile, with immune-related side effects that are generally reversible, making it a valuable option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: A Review in Advanced Melanoma. Deeks, ED.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

In a study of 103 Chinese patients with advanced melanoma, pembrolizumab demonstrated a 16.7% objective response rate, indicating its effectiveness as a second-line treatment, particularly in aggressive melanoma subtypes.

The treatment was well tolerated, with 84.5% of patients experiencing treatment-related adverse events, but only a small percentage (8.7%) had severe side effects, and no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Si, L., Zhang, X., Shu, Y., et al.[2020]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Pembrolizumab, an anti-PD-1 antibody used for treating malignant pleural mesothelioma, can cause serious side effects such as minimal change disease (MCD), which was identified in a 62-year-old patient who developed nephrotic syndrome and acute renal failure after treatment.

The patient's symptoms improved significantly after discontinuing pembrolizumab and starting steroid treatment, highlighting the importance of monitoring renal function and recognizing potential autoimmune reactions in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. Bickel, A., Koneth, I., Enzler-Tschudy, A., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

In the phase 3 KEYNOTE-716 study, adjuvant pembrolizumab significantly improved recurrence-free survival in patients with resected stage IIB and IIC melanoma, demonstrating its efficacy as a treatment option.

Health-related quality of life (HRQoL) remained stable for patients receiving pembrolizumab compared to placebo, with no significant decline in quality of life scores observed, supporting the treatment's manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study. Khattak, MA., Luke, JJ., Long, GV., et al.[2023]

Citations

1. mskcc.org mskcc.org/cancer-care/clinical-trials/23-117

A Phase 2 Study of L19IL2 and L19TNF With ... These drugs bind to tumors, killing cancer cells and activating the immune system to stop and slow tumor growth. Both drugs are injected directly into a tumor.

2. onclive.com onclive.com/view/neoadjuvant-daromun-yields-improved-recurrence-free-survival-in-locally-advanced-melanoma

Neoadjuvant Daromun Yields Improved Recurrence-Free ... Neoadjuvant daromun significantly improved RFS and reduced distant metastasis risk in locally advanced melanoma compared to upfront surgery. The ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0923753425008294

Neoadjuvant intralesional targeted immunocytokines ... This phase III trial assessed daromun, a combination of two fibronectin-targeting immunocytokines (L19IL2 and L19TNF), as a neoadjuvant treatment for patients ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06284590

NCT06284590 | Study of the Efficacy of Intratumoral L19IL2 ... The trial aims to evaluate the efficacy of single agent L19IL2, single agent L19TNF, and combination L19IL2+L19TNF given concurrently with anti-PD1 therapy ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA9501

Phase 3 study (PIVOTAL) of neoadjuvant intralesional ... Daromun, a combination of two antibody-cytokine fusions (L19IL2 and L19TNF) showed efficacy in a phase 2 study (NCT02076633) in unresectable ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11171204/

Intralesional and Infusional Updates for Metastatic Melanoma This article aims to review the current updates and efficacy on intralesional and infusional therapies for locoregionally advanced and metastatic melanoma.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0923753425008294

Neoadjuvant Intralesional Targeted Immunocytokines ... This phase 3 trial assessed daromun, a combination of two fibronectin-targeting immunocytokines (L19IL2 and L19TNF), as a neoadjuvant treatment ...