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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of three immunotherapy drugs for individuals with advanced Merkel cell carcinoma (MCC) that has metastasized and resisted previous treatments. Administered through an IV, these drugs are designed to enhance the immune system's ability to combat cancer. The trial seeks participants with a confirmed diagnosis of advanced MCC that is inoperable and who have previously received but not responded to anti-PD-(L)1 therapy. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant advancements in cancer therapy.

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.

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

Research shows that retifanlimab, one of the treatments being tested, is already approved for treating advanced Merkel cell carcinoma (MCC). This approval confirms its safety in humans and general tolerability. Common side effects include fatigue, skin rash, and diarrhea, though these can vary among individuals.

The other two drugs, tuparstobart and verzistobart, target specific proteins on cancer cells. Earlier studies combining these drugs with a similar method demonstrated that they are generally well-tolerated. Some patients experienced mild to moderate side effects, such as tiredness and nausea.

Overall, while side effects may occur, research suggests that most patients can manage them. Joining the trial might involve regular doctor visits to monitor and address any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of retifanlimab, tuparstobart, and verzistobart for Merkel Cell Carcinoma because it offers a fresh approach to treatment. Unlike traditional therapies that might target the tumor directly, this triple immunotherapy harnesses and boosts the body's immune system to fight the cancer cells more effectively. Retifanlimab is a PD-1 inhibitor, which helps the immune system recognize and attack cancer cells, while tuparstobart and verzistobart further enhance this response, potentially leading to better outcomes. This innovative approach could provide new hope for patients who have limited options with the current standard treatments.

What evidence suggests that this triple immunotherapy could be effective for advanced Merkel cell carcinoma?

Research has shown that retifanlimab, a key drug in this trial, yields promising results for Merkel cell carcinoma (MCC). In one study, 18% of patients experienced a complete response, with their cancer disappearing, and 37% had a partial response, with their tumors shrinking. Thus, more than half of the patients saw their tumors reduce in size. In this trial, participants will receive a combination of three drugs: retifanlimab, tuparstobart, and verzistobart. Tuparstobart and verzistobart enhance the immune system's ability to attack cancer by targeting specific proteins on cancer cells. Early results suggest that this drug combination could benefit patients whose cancer has not responded to other treatments. This combination aims to boost the immune system to halt tumor growth in advanced MCC cases. ^{6 7 8 9 10}

Who Is on the Research Team?

Shailender Bhatia, MBBS

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40796223/

Phase II study of retifanlimab in patients with recurrent ... Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201) · Abstract.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9536

Final results of POD1UM-201, a phase 2 study ... Merkel cell polyomavirus and PD-L1 expression were detectable in 73 (72%) and 83 (82%) patient tumor samples, respectively. Median follow-up ...

3. zynyzhcp.com zynyzhcp.com/mcc/efficacy

Efficacy for MCC | ZYNYZ® (retifanlimab-dlwr) for HCPs ZYNYZ delivered a high tumor response rate with durable responses · A MAJORITY OF PATIENTS ACHIEVED A TUMOR RESPONSE—AND NEARLY 2/3 OF THOSE PATIENTS MAINTAINED ...

4. investor.incyte.com investor.incyte.com/news-releases/news-release-details/phase-3-data-incytes-retifanlimab-zynyzr-patients-squamous-cell

Phase 3 Data for Incyte's Retifanlimab (Zynyz®) in Patients ... Adding retifanlimab to carboplatin and paclitaxel resulted in a clinically meaningful 37% reduction in the risk of progression or death (Hazard ...

5. merkelcell.org merkelcell.org/news-and-publications/2025/phase-ii-study-of-retifanlimab-in-patients-with-recurrent-locally-advanced-or-metastatic-merkel-cell-carcinoma-pod1um-201/

Phase II study of retifanlimab in patients with recurrent locally ... 18 patients (18%) had a complete response to the treatment, meaning their cancer completely disappeared, and 37 patients (37%) had a partial ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/761334Orig1s000correctedlbl.pdf

Zynyz (retifanlimab-dlwr) injection - accessdata.fda.gov Eighty-eight percent of patients had metastatic disease at baseline. Tumor samples were evaluated for Merkel cell polyomavirus (MCPyV): 71% were positive, 23% ...

7. zynyzhcp.com zynyzhcp.com/mcc/

Official HCP Site - ZYNYZ® (retifanlimab-dlwr) for MCC ZYNYZ® (retifanlimab-dlwr) is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). This ...

8. incytemi.com incytemi.com/document/Product%20Resources/Retifanlimab%20SCAC%20Prescribing%20Information%20(May%202025).pdf

ZYNYZ® (retifanlimab-dlwr) — Merkel Cell Carcinoma (MCC) o For the treatment of adult patients with metastatic or recurrent locally advanced MCC. ▫ This indication is approved under ...

9. aetna.com aetna.com/cpb/medical/data/1000_1099/1030.html

Retifanlimab-dlwr (Zynyz) - Medical Clinical Policy Bulletins Retifanlimab safety in this ... FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma.

10. zynyz.com zynyz.com/mcc/

ZYNYZ® (retifanlimab-dlwr) for MCC | Official Patient Site ZYNYZ is a prescription medicine used to treat a type of skin cancer called MCC in adults. ZYNYZ may be used to treat your MCC when it has spread or returned.