Avelumab + Berzosertib for Advanced Cancer

Overseen By Timothy Yap

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, CYP3A4 inducers

Disqualifiers: Brain metastases, Autoimmune disease, Cardiovascular disease, others

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

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

Compensation: Varies

Number of Visits: 7

Duration: 28 days per cycle

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of avelumab with M6620 in treating patients with deoxyribonucleic acid (DNA) damage repair (DDR) deficient solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to damaged DNA and to repair the damage, which can be caused by genetic mutations. 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. M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving avelumab together with M6620 may help to control DDR deficient metastatic or unresectable solid tumors.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot participate if you are currently using strong inhibitors or inducers of CYP3A4 that cannot be stopped before starting the trial and during its duration. Additionally, you should not be on immunosuppressive medication, except for certain permitted steroids.

What data supports the effectiveness of the drug Avelumab + Berzosertib for Advanced Cancer?

Avelumab has shown effectiveness in treating various cancers, including metastatic Merkel cell carcinoma and advanced non-small cell lung cancer, by blocking a protein that helps cancer cells hide from the immune system. While there is no direct data on the combination with Berzosertib, similar combinations of immune checkpoint inhibitors with other drugs have shown promise in enhancing immune response and tumor destruction. ^{1 2 3 4 5}

What safety data exists for Avelumab and Berzosertib in humans?

Avelumab has been studied for safety in various cancers, including Merkel cell carcinoma and non-small cell lung cancer, and is generally considered safe for use in humans. However, specific safety data for the combination of Avelumab and Berzosertib is not provided in the available research. ^{5 6 7 8 9}

What makes the drug combination of Avelumab and Berzosertib unique for treating advanced cancer?

The combination of Avelumab and Berzosertib is unique because Avelumab is an antibody that blocks a protein called PD-L1, helping the immune system attack cancer cells, while Berzosertib is a newer drug that targets a different pathway involved in DNA repair, potentially enhancing the effectiveness of Avelumab in treating advanced cancers. ^{5 6 8 10 11}

Research Team

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with solid tumors that have spread or can't be surgically removed, and are not responding to standard treatments. Participants must have a certain level of physical fitness (ECOG 0-1), adequate organ function, and no severe allergies to study drugs. They should also agree to use effective contraception if applicable.

Inclusion Criteria

My kidney function is within the required range.

I am using effective birth control methods.

You are expected to live for at least 12 more weeks.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I have another cancer that is growing and needs treatment.

I haven't had cancer treatment or radiation in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avelumab IV on days 1 and 15, and M6620 IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 30, 60, and 90 days, then every 12 weeks.

Up to 1 year post treatment

3 visits (in-person) initially, then every 12 weeks

Treatment Details

Interventions

• Avelumab
• Berzosertib

Trial Overview The trial is testing the combination of Avelumab, an immunotherapy drug, with M6620 in patients whose tumors show DNA repair deficiencies. It aims to find the safest dose and see how well these drugs work together against advanced cancers.

Participant Groups

Group I: Treatment (avelumab, M6620) Experimental Treatment 2 Interventions

Patients receive avelumab IV over 60 minutes on days 1 and 15, and M6620 IV over 60 minutes on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a phase 2a trial involving 43 patients with advanced squamous non-small cell lung cancer (NSCLC), the combination of avelumab and cetuximab with chemotherapy resulted in a 34.9% objective response rate, indicating notable antitumor activity.

While the treatment showed tolerable safety, with 88.4% of patients experiencing treatment-related adverse events, the overall response rate was not significantly better than existing standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC. Andric, Z., Gálffy, G., Cobo Dols, M., et al.[2023]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

In the JAVELIN Lung 100 trial involving 1214 patients with advanced NSCLC, avelumab showed longer median progression-free survival (PFS) compared to platinum-based chemotherapy (8.4 months vs. 5.6 months), indicating its potential efficacy as a first-line treatment.

Although avelumab demonstrated longer median overall survival (OS) compared to chemotherapy (20.1 months vs. 14.9 months), the differences were not statistically significant, suggesting that while avelumab may be beneficial, it did not meet the primary objective of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. Reck, M., Barlesi, F., Yang, JC., et al.[2023]

The combination of vibostolimab and pembrolizumab is well tolerated by patients, indicating a favorable safety profile for this treatment regimen.

This combination therapy demonstrates antitumor activity, suggesting it may be an effective option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

Avelumab is an antibody that blocks programmed cell death ligand-1 (PD-L1) and has received accelerated approval in the USA for treating metastatic Merkel cell carcinoma (mMCC) in both adults and children aged 12 and older.

The drug is also undergoing regulatory reviews for other cancer treatments, including urothelial carcinoma, indicating its potential as a versatile cancer therapy in various stages of development worldwide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. Kim, ES.[2022]

Avelumab, a monoclonal antibody targeting PD-L1, demonstrated an acceptable safety profile in a phase 1a trial with 53 patients, with only one dose-limiting toxicity observed at the highest dose of 20 mg/kg, indicating that the maximum tolerated dose was not reached.

The pharmacokinetic analysis showed a dose-proportional exposure and a half-life of approximately 4 days at higher doses, leading to the selection of 10 mg/kg every 2 weeks for further development, as it achieved over 90% target occupancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Heery, CR., O'Sullivan-Coyne, G., Madan, RA., 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]

Avelumab maintenance therapy after platinum-based chemotherapy in advanced urothelial carcinoma significantly improves overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), especially in patients with PD-L1 positive tumors, compared to those receiving best supportive care.

While avelumab is effective, it is associated with a high rate of treatment-related adverse events (TRAEs) in 86.7% of patients, with 32.4% experiencing severe adverse events, indicating the need for careful patient monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes. Ten Eyck, JE., Kahlon, N., Masih, S., et al.[2022]

Immune checkpoint inhibitors like nivolumab, pembrolizumab, and atezolizumab have been shown to improve response rates, overall survival, and quality of life in patients with advanced non-small cell lung cancer (NSCLC) compared to standard chemotherapy.

The use of these agents presents clinical challenges, including managing rare immune-related adverse events and determining optimal treatment duration and patient selection, which are crucial for effective real-world application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint blockade for advanced non-small cell lung cancer: challenging clinical scenarios. Tay, R., Prelaj, A., Califano, R.[2023]

References

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

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC. [2023]

2. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

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

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. [2023]

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

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

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

Avelumab: First Global Approval. [2022]

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

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. [2022]

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

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

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line avelumab in patients with advanced non-small cell lung cancer: results from a phase Ib cohort of the JAVELIN Solid Tumor study. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab and platinum-pemetrexed in patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies: A multicentre phase II open-label non-randomised study GFPC 06-2018. [2023]

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

Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes. [2022]

11. China pubmed.ncbi.nlm.nih.gov

Immune checkpoint blockade for advanced non-small cell lung cancer: challenging clinical scenarios. [2023]