IMC-F106C vs Nivolumab for Melanoma

(PRISM-MEL-301 Trial)

Recruiting at 244 trial locations

Overseen By Immunocore Medical Information EU

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Immunocore Ltd

Must not be taking: Immunosuppressants

Disqualifiers: Other cancers, CNS metastases, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 13

Duration: Up to 51 weeks

680 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for people with advanced melanoma, a serious type of skin cancer. Researchers aim to determine the effectiveness of the experimental drug brenetafusp (also known as IMC-F106C) when combined with nivolumab, a standard treatment, compared to nivolumab alone. Participants will be divided into three groups to test different combinations and doses of these drugs. The trial seeks individuals with advanced melanoma that hasn't been treated yet and who are HLA-A*02:01-positive, a specific genetic marker. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have an active autoimmune disease requiring immunosuppressive treatment, you may not be eligible to participate.

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

Research has shown that brenetafusp (IMC-F106C) is generally well-tolerated. In earlier studies, the most common side effect was a mild form of cytokine release syndrome (CRS), occurring in about half of the participants, mostly during the first three weeks. Importantly, no deaths related to the treatment occurred, although one person stopped treatment due to side effects. Brenetafusp was also found to be safe both on its own and when combined with anti-PD-1 therapies, such as nivolumab.

Nivolumab, already approved by the FDA for various conditions including melanoma, has a well-established safety record. It is generally well-tolerated, though some people might experience side effects like tiredness or a rash. When used with nivolumab, relatlimab has been safely used to treat melanoma, although it may increase the risk of side effects typical of immune therapies.

Overall, based on past research, the treatments in this study have shown reasonable safety, with most patients experiencing manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they bring innovative approaches to tackling the disease. Unlike standard therapies that primarily target immune checkpoints using drugs like nivolumab, brenetafusp offers a fresh mechanism by potentially engaging different immune pathways to enhance the body's fight against cancer. The study explores both low and high doses of brenetafusp combined with nivolumab, aiming to optimize the activation of the immune system. Additionally, including relatlimab in the treatment mix introduces another layer of immune modulation, which could improve outcomes for patients. These treatments are paving the way for more personalized and potentially more effective options for melanoma patients.

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

Research has shown that brenetafusp (IMC-F106C) holds promise for treating advanced melanoma by helping T cells of the immune system attack and enter tumors. Earlier studies found it well tolerated both alone and with anti-PD1 treatments like nivolumab. In this trial, participants in Arm A will receive a low dose of brenetafusp with nivolumab, while those in Arm B will receive a high dose of brenetafusp with nivolumab. Arm C will involve treatment with nivolumab alone or in combination with relatlimab. Previous studies demonstrated long-lasting positive effects, suggesting that brenetafusp, especially with nivolumab, could be effective for people with advanced melanoma. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma who haven't been treated before. They must have a specific genetic marker (HLA-A*02:01), be able to use effective birth control, and have a certain level of physical fitness (ECOG score 0 or 1). People can't join if they have serious lung or heart problems, other cancers, untreated brain metastases, allergies to the drugs being tested, active autoimmune diseases needing treatment, prior cancer therapy for their melanoma, or severe reactions to similar drugs.

Inclusion Criteria

I have a confirmed adequate tumor tissue sample.

My melanoma is at Stage IV or is an unresectable Stage III.

You must have a measurable disease according to specific medical guidelines.

Exclusion Criteria

I have untreated brain metastases or carcinomatous meningitis.

I have a serious lung condition or my lungs don’t work well.

Participants with any medical condition that is poorly controlled or that would, in the Investigator's or Sponsor's judgment, adversely impact the participant's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive brenetafusp (IMC-F106C) plus nivolumab or standard nivolumab regimens

Up to 51 weeks

Weekly visits for the first 13 weeks, then every 2 weeks through Week 51, and every 4 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• IMC-F106C
• Nivolumab
• Relatlimab

Trial Overview The study compares IMC-F106C combined with nivolumab against standard treatments using nivolumab alone or with relatlimab in patients with advanced melanoma. It's randomized and controlled which means participants are placed into groups by chance and compared against each other.

How Is the Trial Designed?

Group I: Arm B: Brenetafusp High Dose + Nivolumab Experimental Treatment 2 Interventions

Participants receive brenetafusp High Dose once weekly (QW) for the first 13 weeks, then every 2 weeks (Q2W) through Week 51, and then every 4 weeks (Q4W). Nivolumab is given Q4W.

Group II: Arm A: Brenetafusp Low Dose + Nivolumab Experimental Treatment 2 Interventions

Participants receive brenetafusp Low Dose once weekly (QW) for the first 13 weeks, then every 2 weeks (Q2W) through Week 51, and then every 4 weeks (Q4W). Nivolumab is given Q4W.

Group III: Arm C: Nivolumab OR Nivolumab + Relatlimab Active Control 2 Interventions

Participants receive nivolumab 480 mg monotherapy, or nivolumab 480 mg + relatlimab 160 mg, Q4W.

Who Is Running the Clinical Trial?

Immunocore Ltd

Lead Sponsor

Trials

17

Recruited

4,400+

Published Research Related to This Trial

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

In a phase 1b trial involving 85 heavily pretreated patients with metastatic cutaneous melanoma, tebentafusp combined with durvalumab and/or tremelimumab showed a promising overall survival rate of 76% at one year, indicating potential efficacy for patients who had previously progressed on checkpoint inhibitors.

The combination therapy was well-tolerated, with no new safety concerns or treatment-related deaths reported, suggesting that tebentafusp can be safely administered alongside existing checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study. Hamid, O., Hassel, JC., Shoushtari, AN., et al.[2023]

Nivolumab showed a higher overall response rate (27% vs. 10%) and a longer median duration of response (32 months vs. 13 months) compared to investigator's choice chemotherapy (ICC) in patients with advanced melanoma who had previously progressed on ipilimumab.

Although the median overall survival was similar between nivolumab (16 months) and ICC (14 months), nivolumab had significantly fewer severe treatment-related adverse events (14% vs. 34%), suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. Larkin, J., Minor, D., D'Angelo, S., et al.[2022]

A multidisciplinary approach using Vedolizumab effectively treated corticosteroid-refractory immune-mediated colitis in a melanoma patient receiving anti-PD-1 therapy, highlighting a potential new treatment strategy for managing immune-related adverse events.

The patient's expression of HLA-B*35 suggests a genetic predisposition to autoimmune reactions, indicating that genotyping may help tailor immunotherapy and manage side effects in high-risk melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report. d'Apolito, M., Spagnuolo, R., Siciliano, MA., et al.[2022]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

In the RELATIVITY-047 trial, the combination of nivolumab and relatlimab (NIVO + RELA) significantly improved progression-free survival in patients with advanced melanoma compared to nivolumab alone, with a median follow-up of 19.3 months.

Despite a higher incidence of severe treatment-related adverse events with the combination therapy, patients reported stable health-related quality of life, indicating that the benefits of NIVO + RELA outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial. Schadendorf, D., Tawbi, H., Lipson, EJ., et al.[2023]

Nivolumab significantly improves recurrence-free survival (RFS) and overall survival (OS) in patients with high-risk resected melanoma compared to a watch-and-wait strategy, with hazard ratios of 0.53 and 0.63, respectively.

In patients with stage IIIB/IIIC melanoma, nivolumab also shows meaningful improvements in distant metastasis-free survival (DMFS) and OS, indicating its effectiveness across different stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma. Weber, JS., Ascierto, PA., Middleton, MR., et al.[2021]

Tebentafusp, approved by the FDA for treating unresectable or metastatic uveal melanoma, activates T cells to induce tumor cell death, showing a 1-year overall survival rate of 73% in Phase III trials with a disease control rate of 46%.

Common side effects include cytokine release syndrome and rash, but the drug's unique mechanism offers a promising alternative for patients with limited treatment options and poor prognosis in this specific type of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tebentafusp: a novel drug for the treatment of metastatic uveal melanoma. Wang, Z., Xie, Y., Wang, JQ., et al.[2023]

The combination of nivolumab and relatlimab, approved by the FDA in 2022, significantly improves progression-free survival in melanoma patients compared to nivolumab alone, with more than a 2-fold increase in median survival time.

These monoclonal antibodies work by blocking PD-1 and LAG-3 proteins, which helps enhance the immune response against melanoma, addressing the challenge of limited patient response due to toxicities and drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and relatlimab for the treatment of melanoma. Chen, XY., Li, YD., Xie, Y., et al.[2023]

Tebentafusp is a groundbreaking bispecific T cell engager that targets HLA-A*02:01-positive uveal melanoma cells, activating T cells to attack and destroy tumor cells, demonstrating its mechanism of action in cancer treatment.

In January 2022, tebentafusp became the first approved treatment for adults with unresectable or metastatic uveal melanoma in the USA, with ongoing regulatory reviews in other countries, highlighting its significance in melanoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tebentafusp: First Approval. Dhillon, S.[2023]

Tebentafusp, a novel bispecific protein targeting the Gp-100 protein in uveal melanoma, has shown an overall survival benefit in a recent phase III trial for patients with untreated metastatic uveal melanoma.

Unlike traditional treatments for cutaneous melanoma, tebentafusp effectively creates an immune response against tumor cells by targeting a specific peptide presented by HLA*A0201, highlighting its unique mechanism of action in this rare cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gp-100 as a Novel Therapeutic Target in Uveal Melanoma. Martinez-Perez, D., Viñal, D., Solares, I., et al.[2021]

In the CheckMate 142 study involving 119 patients with previously treated MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate (ORR) of 55% and a promising 12-month overall survival (OS) rate of 85%.

Most treatment-related adverse events (sTRAEs) were manageable, occurring early and resolving quickly, with comparable efficacy outcomes between patients with and without sTRAEs, indicating a favorable benefit-risk profile for this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Morse, MA., Overman, MJ., Hartman, L., et al.[2020]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

A pharmacovigilance analysis of adverse events from checkpoint inhibitors (CPIs) like ipilimumab, nivolumab, and pembrolizumab revealed that 76% of immune-mediated reactions (IMRs) were associated with ipilimumab, with colitis being the most common IMR (51% of cases).

The study found significant signals for IMRs across all CPIs, particularly strong for colitis (EB05 = 45.6) and pneumonitis (EB05 = 17.6), indicating that while CPIs can be effective in treating various cancers, they also carry a risk of serious immune-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint Inhibitor Cancer Immunotherapies. Ali, AK., Watson, DE.[2018]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9507

Phase 1 safety and efficacy of IMC-F106C, a PRAME × ... IMC-F106C is a novel ImmTAC bispecific protein (PRAME × CD3). Dose escalation results showed robust T cell activation, T cell infiltration into tumor, and ...

2. immunocore.com immunocore.com/investors/news/press-releases/detail/92/immunocore-reports-updated-phase-1-data-of-brenetafusp-imc-f106c-an-immtac-bispecific-targeting-prame-in-immune-checkpoint-pre-treated-cutaneous-melanoma-patients-at-asco-2024

Immunocore reports updated Phase 1 data of brenetafusp ... Brenetafusp was shown to be well tolerated, in monotherapy and in combination with anti-PD1, and demonstrated durable clinical benefit.

3. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A796

694 Phase 1 safety and efficacy of brenetafusp, a PRAME ... Brenetafusp, a PRAMExCD3 ImmTAC bispecific, showed robust T cell activation and infiltration into tumors and activity in various solid tumors.

4. immunocore.com immunocore.com/investors/news/press-releases/detail/94/immunocore-announces-randomization-of-first-patient-in-the-global-registrational-phase-3-clinical-trial-testing-brenetafusp-for-the-treatment-of-first-line-advanced-or-metastatic-cutaneous-melanoma

News The data showed that brenetafusp was well tolerated as monotherapy and in combination with anti-PD1, and demonstrated promising monotherapy ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11631188/

High-affinity T cell receptor ImmTAC® bispecific efficiently ... Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple ...

6. ascopost.com ascopost.com/news/june-2024/clinical-trial-testing-brenetafusp-plus-nivolumab-in-advanced-or-metastatic-cutaneous-melanoma-kicks-off/

Clinical Trial Testing Brenetafusp Plus Nivolumab in ... The data showed that brenetafusp was well tolerated as monotherapy and in combination with anti–PD-1 therapy; the results demonstrated clinical ...

7. researchgate.net researchgate.net/publication/381991111_Phase_1_safety_and_efficacy_of_IMC-F106C_a_PRAME_CD3_ImmTAC_bispecific_in_post-checkpoint_cutaneous_melanoma_CM

Phase 1 safety and efficacy of IMC-F106C, a PRAME × ... Dose escalation results showed robust T cell activation, T cell infiltration into tumor, and clinical activity in various solid tumors ( ...