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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, avelumab (also known as MSB0010718C or Bavencio) and berzosertib (also known as M-6620 or VE-822), to determine the optimal dose and safety for treating certain advanced cancers. These drugs aim to enhance the immune system's ability to attack cancer and inhibit tumor growth, particularly in patients whose cancer cells struggle to repair damaged DNA. The trial targets individuals with solid tumors that have spread or cannot be surgically removed and who have specific genetic changes affecting DNA repair. Those whose cancer has not responded to other treatments and who possess these genetic markers may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that avelumab is usually well tolerated by patients with advanced cancers. Most people experience manageable side effects, and severe side effects related to the treatment are rare. Avelumab has been safely used in other cancers, such as Merkel cell carcinoma and non-small cell lung cancer.

Berzosertib, also known as M6620, is under study as a promising cancer drug. It has been tested both alone and with other treatments. Although complete safety data for its use with avelumab is not yet available, earlier studies suggest it might be safe when used together. Berzosertib alone has also shown potential as a cancer treatment.

In summary, both avelumab and berzosertib have shown promise in treating cancer and are generally considered safe. However, like any treatment, there may be risks of side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avelumab and Berzosertib for advanced cancer because these treatments work differently than standard options like chemotherapy. Avelumab is an immunotherapy that activates the immune system to attack cancer cells, offering a targeted approach. Berzosertib inhibits a protein called ATR, which is involved in DNA repair, making cancer cells more vulnerable to damage. This combination could potentially enhance treatment effectiveness by both directly attacking cancer cells and boosting the body's natural defenses.

What evidence suggests that this trial's treatments could be effective for DDR deficient metastatic or unresectable solid tumors?

Research has shown that avelumab effectively treats several types of cancer, including advanced Merkel cell carcinoma and non-small cell lung cancer. Avelumab helps the immune system attack cancer cells, stopping their growth and spread. In this trial, participants will receive a combination of avelumab and berzosertib. Berzosertib may enhance avelumab's effect by blocking enzymes that cancer cells need for growth. Early studies suggest that combining avelumab with berzosertib might improve outcomes for patients with tumors that struggle to repair DNA damage. This combination could be especially promising for tumors that have spread or cannot be surgically removed. ^{1 3 4 6 7}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Expansion Dose Level 2 Experimental Treatment 2 Interventions

Berzosertib 480 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Group II: Expansion Dose Level 1 Experimental Treatment 2 Interventions

Berzosertib 240 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Group III: Escalation Dose Level 2 Experimental Treatment 2 Interventions

Berzosertib 480 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

Group IV: Escalation Dose Level 1 Experimental Treatment 2 Interventions

Berzosertib 240 mg/m2 once weekly + Avelumab 800 mg IV on days 1 and 15 of each 28-day cycle

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+

Published Research Related to This Trial

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, 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]

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]

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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-2-neoplasms-2-2020-4ee58

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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7252959/

Efficacy and safety of avelumab treatment in patients with ... Avelumab, a human anti–programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel ...

3. bavencio.com bavencio.com/en_US/patients-and-caregivers/mcc-home/clinical-study-results.html

Clinical Study Results | BAVENCIO® (avelumab) Efficacy BAVENCIO is not a cure. The data represent patients in the clinical trial, and not all patients will experience the same results.

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/12/NCT04266912/Prot_SAP_000.pdf

mdacc # 2018-1059 of the combination of M6620 and avelumab in patients with DDR deficient advanced solid tumors. Secondary objectives: 1. To determine the ...

5. researchgate.net researchgate.net/publication/334218714_Abstract_2269_ATR_inhibitor_M6620_enhances_anti-tumor_efficacy_of_the_combination_of_the_anti-PD-L1_antibody_avelumab_with_platinum-based_chemotherapy

ATR inhibitor M6620 enhances anti-tumor efficacy of the ... We investigated anti-tumor efficacy of carboplatin or cisplatin in combination with M6620 and avelumab in MC38 murine colorectal tumor model.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5947549/

Safety profile of avelumab in patients with advanced solid ... Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and ...

7. sciencedirect.com sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/berzosertib

Berzosertib - an overview The results suggest that VX-970 is indeed a promising anticancer drug that can be used both as monotherapy and in combination with either chemotherapy or ...