Triple Immunotherapy for Merkel Cell Carcinoma

(TRICK-MCC Trial)

Overseen By Shailender Bhatia, MBBS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must be taking: Anti-PD-(L)1

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: CNS metastases, Active autoimmune, Cardiovascular, 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: 13

12 Participants Needed

Trial Summary

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 are on medications that could interfere with the study or put your safety at risk, you may need to discuss this with the trial investigators. It's best to consult with them for specific guidance.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to understand any potential interactions.

What data supports the idea that Triple Immunotherapy for Merkel Cell Carcinoma is an effective treatment?

The available research shows that while PD-1 pathway blocking agents like avelumab, pembrolizumab, and nivolumab have shown high rates of long-lasting responses in some patients with Merkel Cell Carcinoma (MCC), about half of the patients do not benefit from these treatments. This indicates a need for new strategies, such as Triple Immunotherapy, to improve outcomes. Additionally, a study involving patients who did not respond to PD-1 treatments found that some experienced tumor shrinkage when treated with a combination of other immune therapies, suggesting that Triple Immunotherapy could potentially be effective for those who do not respond to existing treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Retifanlimab and its related treatments for Merkel Cell Carcinoma?

Research shows that drugs blocking the PD-1/PD-L1 pathway, like avelumab, have led to durable responses in some patients with advanced Merkel Cell Carcinoma. However, about half of the patients do not benefit from these treatments, indicating a need for new strategies, such as the triple immunotherapy being tested. ^{1 2 3 4 5}

What safety data is available for triple immunotherapy in Merkel Cell Carcinoma?

The provided research does not directly address the safety data for the specific triple immunotherapy treatment involving Retifanlimab or its other names. However, it does highlight the use of PD-1/PD-L1 inhibitors like avelumab in Merkel Cell Carcinoma (MCC) and notes the potential for immune-related adverse events (irAEs), particularly in patients with preexisting autoimmune conditions. The research also mentions that PD-1 pathway blockade has shown durable responses in some MCC patients, but approximately 50% do not benefit persistently, indicating a need for novel strategies. For specific safety data on the triple immunotherapy treatment, further investigation into clinical trials involving Retifanlimab and its related compounds would be necessary. ^{2 4 6 7 8}

Is triple immunotherapy for Merkel Cell Carcinoma safe for humans?

The safety of PD-1/PD-L1 inhibitors, which are part of the triple immunotherapy for Merkel Cell Carcinoma, has been studied, showing that they can cause immune-related side effects, especially in people with preexisting autoimmune diseases. These side effects can be serious, including neurological issues, so it's important to discuss potential risks with your doctor. ^{2 4 6 7 8}

Is the drug Retifanlimab a promising treatment for Merkel Cell Carcinoma?

Yes, Retifanlimab is a promising drug for treating Merkel Cell Carcinoma. It has received accelerated approval for treating advanced cases of this rare skin cancer, showing that it can be effective in helping patients. ^{2 3 9 10 11}

How does the drug Retifanlimab differ from other treatments for Merkel cell carcinoma?

Retifanlimab is unique because it is a PD-1 receptor-blocking antibody specifically approved for treating Merkel cell carcinoma, offering a new option for patients who may not respond to traditional chemotherapy or other immunotherapies. It works by helping the immune system recognize and attack cancer cells, which is particularly important for this aggressive skin cancer. ^{2 3 9 10 11}

What is the purpose of this trial?

This phase II trial tests how well a combination of three immunotherapy drugs work for patients with Merkel cell carcinoma that has spread to lymph nodes and/or distant parts of the body and cannot be treated with surgery (advanced or metastatic MCC) and grew despite prior PD-(L)1 therapy. The three drugs INCMGA00012 (retifanlimab, anti-PD-1), INCAGN02385 (tuparstobart, anti-LAG-3), and INCAGN02390 (verzistobart, anti-TIM-3) are monoclonal antibodies given periodically via IV to reactivate the body's immune system to attack the cancer. This combination may stop tumor growth if tumors have grown despite anti-PD-(L)1 therapy alone.

Research Team

Shailender Bhatia, MBBS

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Adults with advanced or metastatic Merkel Cell Carcinoma that worsened after anti-PD-(L)1 therapy, who've had at least one systemic treatment. They must be in relatively good health, not pregnant, willing to use contraception and consent to tumor biopsies. Excluded are those with autoimmune diseases, severe illnesses affecting immunity, certain heart conditions, active infections like HIV/HBV/HCV or brain metastases.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

Your hemoglobin level is at least 9 grams per deciliter, even if you have had a blood transfusion.

I have at least one measurable Merkel cell carcinoma tumor.

Exclusion Criteria

I am not allergic to any part of the study drugs.

I have a weakened immune system due to severe diabetes, blood cancer, or other serious health issues.

I have stable brain metastases and haven't needed steroids for them in the last 7 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Patients receive anti-LAG-3 and anti-TIM-3 intravenously every 2 weeks and retifanlimab every 4 weeks, with clinical visits, physical examinations, and labs for safety. CT/MRI every 8 weeks. Research tumor biopsies and blood draws are conducted.

24 weeks

Bi-weekly visits (in-person)

Maintenance

Patients receive all three drugs intravenously every 6 weeks, with clinical visits, physical examinations, and labs for safety. CT/MRI every 12 weeks. Research blood sample collection continues periodically.

78 weeks

Every 6 weeks (in-person)

Follow-up

Participants are monitored for long-term outcomes every 6 months for up to 5 years after completion of study treatment.

Up to 5 years

Every 6 months (in-person)

Treatment Details

Interventions

• Retifanlimab
• Tuparstobart
• Verzistobart

Trial Overview The trial is testing a combination of three immunotherapy drugs (retifanlimab, tuparstobart, verzistobart) given via IV for patients whose cancer has spread and didn't respond to previous treatments. These drugs aim to boost the immune system's ability to fight cancer by targeting different checkpoints on immune cells.

Participant Groups

Group I: Treatment (retifanlimab, tuparstobart, and verzistobart) Experimental Treatment 7 Interventions

INDUCTION PHASE: Patients receive retifanlimab IV over 30 minutes every 4 weeks and tuparstobart and verzistobart IV over 30 minutes every 2 weeks. Treatment continues for up to day 169 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography CT/MRI during screening and on study and blood sample collection on study and may undergo during screening. Patients may also undergo a tumor biopsy during screening and on study. MAINTENANCE PHASE: Patients receive retifanlimab, tuparstobart and verzistobart IV over 30 minutes every 6 weeks. Treatment continues for up to day 715 in the absence of disease progression or unacceptable toxicity. Patients undergo CT/MRI on study and blood sample collection on study and may undergo during follow-up. Patients may also undergo tumor biopsy on study and during follow-up.

Retifanlimab is already approved in United States for the following indications:

Approved in United States as Zynyz for:

• Merkel cell carcinoma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

In a phase II trial involving 116 patients with metastatic Merkel cell carcinoma (mMCC), first-line treatment with avelumab resulted in a 39.7% objective response rate and a 30.2% durable response rate, indicating its efficacy in this aggressive skin cancer.

The treatment was generally well-tolerated, with 81% of patients experiencing treatment-related adverse events, but only 18.1% had severe (grade 3/4) events, and there were no treatment-related deaths, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. D'Angelo, SP., Lebbé, C., Mortier, L., et al.[2022]

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer, with current chemotherapy options providing durable responses in less than 10% of cases, highlighting the urgent need for better treatments.

Recent clinical trials using PD-1 pathway blockade (with agents like avelumab, pembrolizumab, and nivolumab) have shown high rates of durable responses in advanced MCC, leading to the first FDA approval for this disease, although about 50% of patients still do not benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes. Colunga, A., Pulliam, T., Nghiem, P.[2019]

In a retrospective case series of 13 patients with Merkel cell carcinoma (MCC) who progressed after anti-PD-1 therapy, 31% showed objective responses to subsequent treatment with anti-CTLA-4, indicating potential efficacy of this approach.

This study also reports the first instance of tumor regression in a patient with anti-PD-1-refractory MCC treated with a PD-L1 antibody, suggesting that alternative immune checkpoint therapies may activate anti-tumor immunity in resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series. LoPiccolo, J., Schollenberger, MD., Dakhil, S., et al.[2023]

In a study of 88 patients with metastatic Merkel cell carcinoma (mMCC) treated with avelumab, the objective response rate was 33%, with a median duration of response lasting 40.5 months, indicating significant long-term efficacy.

The long-term safety profile of avelumab was favorable, with no new adverse events reported and no treatment-related deaths, supporting its use as a standard treatment for mMCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. D'Angelo, SP., Bhatia, S., Brohl, AS., et al.[2021]

Merkel cell carcinoma, a rare and aggressive skin cancer linked to UV exposure and the Merkel-cell polyomavirus, often expresses PD-L1, making PD-1/PD-L1 checkpoint therapies promising treatment options.

Despite the potential of these therapies, only about 50% of advanced Merkel cell carcinoma patients achieve remission or stabilization, indicating a need for innovative treatments in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Landscape of current and future therapies of Merkel cell carcinoma. Kwiatkowska, D., Reich, A.[2021]

Patients with metastatic Merkel cell carcinoma (mMCC) reported a more positive experience with avelumab compared to their previous chemotherapy, indicating improved patient satisfaction.

Qualitative interviews and the FACT-M questionnaire revealed that most patients experienced either stable or improved symptoms while on avelumab, with some noting reduced toxicity compared to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of avelumab versus chemotherapy in Merkel cell carcinoma: innovative use of patient insights. Bharmal, M., Marrel, A., Hennessy, M., et al.[2020]

A 61-year-old woman with advanced Merkel cell carcinoma and a history of myasthenia gravis was treated with the PD-1 inhibitor pembrolizumab, resulting in a partial response and long-lasting tumor remission without exacerbation of her myasthenia gravis.

This case suggests that patients with preexisting autoimmune conditions like myasthenia gravis can be considered for PD-1 inhibitor therapy in life-threatening cancer situations, but careful monitoring and a multidisciplinary approach are essential due to the risk of severe immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors? Zaremba, A., Chorti, E., Jockenhöfer, F., et al.[2020]

Two patients with BRAF V600E mutant melanoma treated with anti-PD-1 agents experienced no significant toxicity, highlighting the favorable safety profile of these immune checkpoint inhibitors as first-line therapy.

However, both patients developed severe hypersensitivity reactions and multi-organ injury after starting vemurafenib, indicating that clinicians should be cautious and monitor for potential toxicities when transitioning from anti-PD-1 therapy to BRAF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Johnson, DB., Wallender, EK., Cohen, DN., et al.[2021]

Retifanlimab is a programmed cell death 1 (PD-1) receptor-blocking antibody developed for treating solid tumors, showing promise both alone and in combination with other therapies.

It has received accelerated approval for adults with metastatic or recurrent locally advanced Merkel cell carcinoma, marking a significant milestone in its development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retifanlimab: First Approval. Kang, C.[2023]

Merkel cell carcinoma (MCC) tumors can be targeted for immune therapy, as they show sensitivity to immune cell lysis, particularly when treated with INFγ to enhance the expression of key antigens like HLA-I and ICAM-1.

The study identified anti-CD326 (EpCAM) as the only antibody that effectively induced antibody-dependent cellular cytotoxicity (ADCC) against MCC lines, suggesting that targeting EpCAM could be a promising strategy for enhancing treatment efficacy in MCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Merkel cell carcinoma and cellular cytotoxicity: sensitivity to cellular lysis and screening for potential target antigens suitable for antibody-dependent cellular cytotoxicity. Ollier, J., Kervarrec, T., Samimi, M., et al.[2019]

In a case report involving 5 patients with metastatic Merkel cell carcinoma (MCC), treatment with VEGFR tyrosine kinase inhibitors (TKIs) like pazopanib and cabozantinib showed clinical benefits, including one complete response and disease stabilization lasting from 5 months to 3.5 years.

The use of VEGFR-TKIs was well-tolerated, with no unusual toxicities reported, suggesting they could be a promising treatment option for patients with MCC, particularly those who do not respond to immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients. Tarabadkar, ES., Thomas, H., Blom, A., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Landscape of current and future therapies of Merkel cell carcinoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of avelumab versus chemotherapy in Merkel cell carcinoma: innovative use of patient insights. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors? [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Retifanlimab: First Approval. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Merkel cell carcinoma and cellular cytotoxicity: sensitivity to cellular lysis and screening for potential target antigens suitable for antibody-dependent cellular cytotoxicity. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients. [2021]