Berzosertib + Irinotecan for Gastric Cancer

Not currently recruiting at 35 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Early stage cancer, Brain metastases, Allergic reactions, 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

Compensation: Varies

Number of Visits: 2

Duration: Up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining berzosertib and irinotecan for individuals with stomach cancer or cancer at the junction of the stomach and esophagus. The aim is to determine if this combination can halt the growth, spread, or worsening of cancer, particularly when surgery is not an option. Berzosertib may block proteins that enable cancer cell growth, while irinotecan is a chemotherapy drug that kills cancer cells or prevents their division. The trial seeks participants whose cancer has progressed despite previous treatments and who have a specific genetic mutation known as a TP53 mutation. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it advises avoiding certain drugs that interact with the trial medications. You should discuss your current medications with the study team to ensure there are no interactions.

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

Research has shown that berzosertib combined with irinotecan appears safe for patients with certain types of stomach cancer. Studies have found that this combination causes side effects, but they are usually mild enough for patients to continue treatment. Irinotecan alone is known to cause side effects that can be managed with proper care. Researchers are testing whether using both drugs together is more effective than using irinotecan alone. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for gastric cancer?

Most treatments for gastric cancer, like chemotherapy, target rapidly dividing cells but often affect healthy cells too. Berzosertib is unique because it specifically targets the ATR pathway, a key player in DNA damage repair, which is often overactive in cancer cells. Researchers are excited about the combination of berzosertib with irinotecan because it may enhance the effectiveness of irinotecan by preventing cancer cells from repairing the DNA damage caused by the chemotherapy. This targeted approach could mean better outcomes with potentially fewer side effects compared to traditional chemotherapy options.

What evidence suggests that berzosertib and irinotecan might be an effective treatment for gastric cancer?

This trial will evaluate the combination of berzosertib and irinotecan for treating stomach and gastroesophageal junction cancer. Research has shown that berzosertib with irinotecan might be more effective than irinotecan alone. Studies have found this combination particularly promising for patients with TP53 mutations, which are common in these cancers. Berzosertib stops enzymes that allow tumor cells to grow, while irinotecan directly attacks and kills cancer cells. Together, they enhance the treatment's effectiveness against tumors. Early results suggest this combination is generally safe and could offer a new treatment option for patients with advanced cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Jordan D Berlin

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults over 18 with progressive, metastatic, or unresectable gastric or gastroesophageal junction cancer that has a TP53 mutation. Participants must have tried at least two systemic therapies and meet certain health criteria (like blood cell counts). Women of childbearing age and men with partners of childbearing age must use contraception.

Inclusion Criteria

Leukocytes >= 3,000/mcL.

Absolute neutrophil count >= 1,500/mcL.

Hemoglobin >= 9 g/dL.

Exclusion Criteria

I do not have untreated or symptomatic brain metastases.

I haven't had any cancer besides local ones in the past 3 years.

I still have side effects from cancer treatment that are not hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive irinotecan IV over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 1 year

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 2 months for up to 1 year.

1 year

Follow-up visits every 2 months

What Are the Treatments Tested in This Trial?

Interventions

• Berzosertib
• Irinotecan

Trial Overview The trial is testing the effectiveness of combining berzosertib, which blocks enzymes needed for tumor growth, with irinotecan, a chemotherapy drug that kills or stops the spread of cancer cells. The goal is to see if this combination works better than irinotecan alone in treating these cancers.

How Is the Trial Designed?

Group I: Treatment (irinotecan and M6620) Experimental Treatment 5 Interventions

Patients receive irinotecan IV over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo endoscopic or CT assisted biopsy and MRI on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The maximum-tolerated dose (MTD) of irinotecan (CPT-11) combined with cisplatin for treating advanced gastric cancer was determined to be 80 mg/m2, with neutropenia identified as the primary dose-limiting toxicity.

The treatment regimen resulted in a partial response in 10 out of 24 patients, leading to an overall response rate of 41.7%, indicating that this combination therapy is effective and warrants further investigation in phase II studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. Shirao, K., Shimada, Y., Kondo, H., et al.[2018]

In a study of 23 patients with advanced gastric cancer, the combination therapy of irinotecan (CPT-11) and S-1 resulted in a promising overall response rate of 47.8% and a median time to progression of 210 days.

The treatment was associated with low rates of severe toxicity, with only 17.4% experiencing grade 3 or 4 hematological issues and 8.7% facing non-hematological toxicity, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). Uedo, N., Narahara, H., Ishihara, R., et al.[2018]

In a late phase II study involving 81 patients with advanced gastric cancer, irinotecan hydrochloride (CPT-11) demonstrated an overall response rate of 23.3% among evaluable cases, indicating its potential efficacy in this patient population.

The treatment was associated with significant toxicities, including leukopenia (41.2%) and anemia (28.9%), but these were generally reversible, suggesting that while CPT-11 is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group]. Futatsuki, K., Wakui, A., Nakao, I., et al.[2018]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03641313

Study Details | Berzosertib and Irinotecan in Treating ... Giving berzosertib and irinotecan may work better than irinotecan alone in treating patients with gastric and gastroesophageal junction cancer. Detailed ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.4044

A phase 2 single-arm study of berzosertib in combination ... We evaluated irinotecan in combination with the ATR inhibitor berzosertib (formerly M6620) in patients with TP53-mutated gastric and GEJ adenocarcinoma.

3. aacrjournals.org aacrjournals.org/mct/article/20/12_Supplement/P032/675916/Abstract-P032-Berzosertib-plus-irinotecan-in

Abstract P032: Berzosertib plus irinotecan in patients with ... Conclusion: Berzosertib plus irinotecan appears to be safe in patients with TP53 mutated gastric/GEJ adenocarcinoma. The interim efficacy ...

4. withpower.com withpower.com/trial/phase-3-esophageal-neoplasms-5-2020-41241

Berzosertib + Irinotecan for Gastric Cancer Research shows that Irinotecan, when combined with other drugs like S-1 or cisplatin, has shown some effectiveness in treating advanced gastric cancer, with ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.3012

NCI 9938: Phase I clinical trial of ATR inhibitor berzosertib ... Berzosertib 270 mg/m 2 - irinotecan 180 mg/m 2 was declared the RP2D. The combination is associated with manageable side effects and promising disease activity.