Tuvusertib + Avelumab for Merkel Cell Skin Cancer

Recruiting at 50 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton-pump inhibitors, CYP3A4 inhibitors

Disqualifiers: Ataxia telangiectasia, Uncontrolled illness, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 23

Duration: 21-day cycles, repeated until disease progression or unacceptable toxicity

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications if they interact with the trial drugs. Specifically, you cannot take strong inhibitors or inducers of certain enzymes (like CYP3A4 and CYP1A2) or certain other drugs like metformin and ciprofloxacin. It's important to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug avelumab for treating Merkel cell skin cancer?

Avelumab has been shown to be effective in treating metastatic Merkel cell carcinoma, with about one-third of patients experiencing a positive response, and many of these responses lasting at least 12 months. It is the first drug specifically approved for this type of cancer, offering a new treatment option for this aggressive disease. ^{1 2 3 4 5}

Is the combination of Tuvusertib and Avelumab safe for treating Merkel Cell Skin Cancer?

Avelumab, used for treating Merkel Cell Carcinoma, has been shown to have an acceptable and manageable safety profile, with some risk of immune-related side effects. However, specific safety data for the combination of Tuvusertib and Avelumab is not provided in the available research. ^{1 2 3 4 6}

How is the drug Tuvusertib + Avelumab unique for treating Merkel cell skin cancer?

Avelumab is unique as it was the first approved drug specifically for metastatic Merkel cell carcinoma, working as an immune checkpoint inhibitor to help the immune system attack cancer cells. The combination with Tuvusertib, although not detailed in the research, suggests a novel approach potentially enhancing the effectiveness of Avelumab. ^{1 2 3 5 6}

What is the purpose of this trial?

This phase II trial compares tuvusertib in combination with avelumab to tuvusertib alone to determine whether the combination therapy will lengthen the time before the cancer starts getting worse in patients with Merkel cell cancer that has not responded to previous treatment (refractory). Tuvusertib is a drug that inhibits an enzyme called ataxia telangiectasia and Rad3 related (ATR) kinase, which is an enzyme that plays a role in repair of damaged deoxyribonucleic acid (DNA) as well as tumor cell replication and survival. It may lead to tumor cell death by inhibiting ATR kinase activity. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tuvusertib in combination with avelumab may lengthen the time before Merkel cell cancer starts getting worse compared to giving avelumab alone.

Research Team

Paul Nghiem

Principal Investigator

Fred Hutchinson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or metastatic Merkel cell carcinoma who have previously been treated with anti-PD-1 or anti-PD-L1 therapy without success. Participants must be over 18, have a certain level of physical fitness (ECOG <=2), and meet specific blood count and organ function criteria.

Inclusion Criteria

I have been diagnosed with advanced or metastatic Merkel cell carcinoma.

I can take care of myself but might not be able to do heavy physical work.

Your liver enzyme levels are not more than three times the normal limit.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive tuvusertib orally once daily on days 1-14 of each 21-day cycle. In Arm 2, participants also receive avelumab intravenously on day 1 of each cycle.

21-day cycles, repeated until disease progression or unacceptable toxicity

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 6 months for 2 years.

2 years

1 visit at 30 days, then every 6 months

Treatment Details

Interventions

• Avelumab
• Biopsy
• Biospecimen Collection
• Computed Tomography
• Magnetic Resonance Imaging
• Positron Emission Tomography
• Tuvusertib

Trial Overview The MATRiX trial is testing the combination of Tuvusertib, which blocks an enzyme involved in DNA repair and tumor survival, with Avelumab, an immunotherapy drug that may help the immune system fight cancer. The goal is to see if this combo works better than just Avelumab alone for controlling disease progression.

Participant Groups

Group I: Arm 2 (tuvusertib, avelumab) Experimental Treatment 7 Interventions

Patients receive tuvusertib PO QD on days 1-14 of each cycle and avelumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool at screening and on study.

Group II: Arm 1 (tuvusertib) Active Control 6 Interventions

Patients receive tuvusertib PO QD on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool at screening and on study. Patients with documented progression may cross over to Arm 2.

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Avelumab is a monoclonal antibody that effectively treats metastatic Merkel cell carcinoma (MCC), showing an objective response rate of 31.8% in a phase II trial with 88 previously treated patients, including 10 complete responses.

The treatment demonstrated a median overall survival of 12.9 months and a 1-year progression-free survival rate of 30%, with manageable side effects, making it a promising alternative to traditional chemotherapy for MCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. Joseph, J., Zobniw, C., Davis, J., et al.[2020]

Avelumab is the first approved treatment specifically for metastatic Merkel cell carcinoma (MCC), showing significant efficacy with about one-third of chemotherapy-refractory patients responding positively, and 74% of these responses lasting at least 12 months.

In a separate cohort of chemotherapy-naïve patients, avelumab demonstrated an impressive objective response rate of over 60%, while maintaining a manageable safety profile despite some risk of immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: A Review in Metastatic Merkel Cell Carcinoma. Shirley, M.[2020]

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]

In a study of 14 patients with advanced Merkel cell carcinoma who were resistant to the PD-L1 inhibitor avelumab, treatment with ipilimumab plus nivolumab (IPI/NIVO) resulted in a 50% overall response rate, indicating significant efficacy in this challenging patient population.

After a median follow-up of nearly 19 months, the treatment showed promising progression-free survival (PFS) and overall survival (OS) rates, with 12-month PFS at 42.9% and a 36-month OS rate of 64.3%, suggesting durable benefits from IPI/NIVO even in patients previously resistant to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG. Glutsch, V., Schummer, P., Kneitz, H., et al.[2022]

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]

Avelumab, a PD-L1 inhibitor, has shown overall response rates for advanced Merkel cell carcinoma (MCC) ranging from 29.1% to 72.1% in real-world studies, with median progression-free survival between 8.1 to 24.1 months, indicating its efficacy across diverse populations.

The treatment is generally safe, with common side effects including fatigue and infusion-related reactions, and it appears to be particularly effective in immunosuppressed patients, although further research is needed to evaluate long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab for Advanced Merkel Cell Carcinoma: Global Real-World Data on Patient Response and Survival. Lohray, R., Verma, KK., Wang, LL., et al.[2023]

References

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

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. [2020]

2. France pubmed.ncbi.nlm.nih.gov

Avelumab: A Review in Metastatic Merkel Cell Carcinoma. [2020]

3. 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]

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

Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG. [2022]

5. 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]

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

Avelumab for Advanced Merkel Cell Carcinoma: Global Real-World Data on Patient Response and Survival. [2023]