Immunotherapy + Chemotherapy for Gastrointestinal Cancer

(EDGE-Gastric Trial)

Recruiting at84 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: Arcus Biosciences, Inc.

Must not be taking: Immune checkpoint inhibitors

Disqualifiers: Brain metastases, HER-2 positive, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and preliminary clinical activity of treatment combinations with and without chemotherapy in participants with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma. Chemotherapy will consist of FOLFOX (oxaliplatin, leucovorin, fluorouracil).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination used in the Immunotherapy + Chemotherapy for Gastrointestinal Cancer trial?

Research shows that combining oxaliplatin with 5-fluorouracil (5-FU) and leucovorin significantly improves response rates and survival in patients with advanced colorectal cancer. This suggests that similar combinations could be effective for gastrointestinal cancers. ^{1 2 3 4 5}

What safety data exists for the combination of fluorouracil, leucovorin, and oxaliplatin in cancer treatment?

The combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is generally safe but can cause side effects like low white blood cell counts (neutropenia), nerve damage (neuropathy), nausea, diarrhea, and mouth sores. Some patients may experience severe side effects, and allergic reactions are rare but possible. ^{2 5 6 7 8}

What makes the drug combination of Domvanalimab, Fluorouracil, Leucovorin, Oxaliplatin, and Zimberelimab unique for gastrointestinal cancer?

This treatment is unique because it combines immunotherapy (Domvanalimab and Zimberelimab) with chemotherapy (Fluorouracil, Leucovorin, and Oxaliplatin), potentially enhancing the immune system's ability to fight cancer while also directly targeting cancer cells, which is different from standard chemotherapy regimens that do not include immunotherapy. ^{5 9 10 11 12}

Research Team

Medical Director

Principal Investigator

Arcus Biosciences, Inc.

Eligibility Criteria

Adults with advanced cancers of the upper gastrointestinal tract, specifically gastric, GEJ, and esophageal adenocarcinoma that can't be surgically removed or has spread. They should be relatively active (ECOG score 0-1), have a life expectancy of at least 3 months, measurable cancer lesions, good organ function, and provide a tumor sample for testing.

Inclusion Criteria

I have advanced stomach or esophagus cancer and am expected to live at least 3 more months.

At least one measurable target lesion per RECIST v1.1

I can provide a sample of my cancer for testing.

Exclusion Criteria

Participants with underlying medical conditions that, in the Investigator's or Sponsor's opinion, will make the administration of investigational products hazardous

I am in Cohort A and my tumor is HER-2 positive.

I stopped previous immune therapy due to side effects; I've had anti-TIGIT treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment combinations with and without chemotherapy, including FOLFOX and immunotherapy agents like domvanalimab and zimberelimab

12-24 weeks

Bi-weekly visits for chemotherapy, monthly visits for immunotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• Domvanalimab (Monoclonal Antibodies)
• Fluorouracil (Alkylating agents)
• Leucovorin (Folate Analogues)
• Oxaliplatin (Alkylating agents)
• Zimberelimab (Monoclonal Antibodies)

Trial Overview The study is testing combinations of new drugs Quemliclustat, Zimberelimab, Domvanalimab with/without standard chemotherapy FOLFOX (Fluorouracil + Leucovorin + Oxaliplatin) in three different groups to see which works best for treating these cancers.

Participant Groups

Group I: Cohort C1: Second Line or greater - Checkpoint Inhibitor Experienced Participants Experimental Treatment 2 Interventions

Domvanalimab and zimberelimab Q3W administered by IV infusion

Group II: B2: Second Line or greater Checkpoint Inhibitor Naïve Participants Experimental Treatment 2 Interventions

Quemliclustat Q2W and zimberelimab Q4W administered by IV infusion

Group III: B1: Second Line or greater Checkpoint Inhibitor Naïve Participants Experimental Treatment 2 Interventions

Domvanalimab and zimberelimab administered once every three weeks (Q3W) by IV infusion

Group IV: A4 First Line - Treatment Naïve Participants Experimental Treatment 4 Interventions

Zimberelimab administered Q4W via IV infusion over 30 minutes, in addition to FOLFOX chemotherapy via IV infusion Q2W

Group V: A3 First Line - Treatment Naïve Participants Experimental Treatment 5 Interventions

Non-randomized A3 safety run-in cohort: Domvanalimab and zimberelimab co-administered Q4W via IV infusion over 60 minutes in addition to FOLFOX chemotherapy via IV infusion Q2W. After completion of A3 safety run-in cohort, participants are randomized to the A3 arm. Domvanalimab and zimberelimab co-administered Q4W via IV infusion over 30 minutes, in addition to FOLFOX chemotherapy via IV infusion Q2W

Group VI: A2: First Line - Treatment Naïve Participants Experimental Treatment 4 Interventions

Zimberelimab Q4W in addition to chemotherapy with FOLFOX administered by IV infusion Q2W

Group VII: A1: First Line - Treatment Naïve Participants Experimental Treatment 5 Interventions

Domvanalimab and zimberelimab once every 4 weeks (Q4W) in addition to FOLFOX chemotherapy by intravenous (IV) infusion once every 2 weeks (Q2W)

Who Is Running the Clinical Trial?

Arcus Biosciences, Inc.

Lead Sponsor

Trials

44

Recruited

7,500+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Findings from Research

The combination of oxaliplatin and irinotecan with continuous infusion of 5FU has significantly improved treatment outcomes for metastatic colorectal cancer, leading to better response rates and overall survival compared to earlier treatments.

The ongoing trials, such as Optimox2, are exploring strategies to reduce treatment cycles and toxicity while maintaining efficacy, alongside promising new targeted therapies against EGFR and VEGF, which could further enhance treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Reflexion on a good strategy of use of oxaliplatine with 5-fluorouracil and its derivatives in patients with advanced colorectal cancer]. Tournigand, C., de Gramont, A.[2018]

In a study of 11 patients with advanced or metastatic colorectal cancer, the FOLFOX4 regimen showed a 0% response rate, while mFOLFOX6 had a 71% response rate as a first-line therapy, indicating that mFOLFOX6 is more effective.

Patients who responded to FOLFOX4/mFOLFOX6 or FOLFIRI had significantly longer survival times (7 to 27 months) compared to those who did not respond (4 to 8 months), suggesting that these treatments can be effective for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of fluorouracil, leucovorin plus oxaliplatin (FOLFOX4 and modified FOLFOX6) followed by fluorouracil, leucovorin plus irinotecan(FOLFIRI)for advanced or metastatic colorectal cancer--case studies. Ohtani, H., Arimoto, Y., Nishio, K., et al.[2016]

In a phase III study involving 220 previously untreated patients with metastatic colorectal cancer, both treatment sequences (FOLFIRI followed by FOLFOX6 and vice versa) resulted in similar median survival rates of approximately 21.5 months and 20.6 months, indicating comparable efficacy.

The study revealed distinct toxicity profiles for each treatment sequence, with FOLFIRI causing more mucositis and nausea/vomiting, while FOLFOX6 was associated with higher rates of neutropenia and neurosensory toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. Tournigand, C., André, T., Achille, E., et al.[2023]

In a phase III study of 220 previously untreated patients with metastatic colorectal cancer, both treatment sequences (FOLFIRI followed by FOLFOX6 and vice versa) resulted in similar median survival rates of approximately 21.5 months and 20.6 months, indicating comparable efficacy.

The study revealed distinct toxicity profiles for the two treatment sequences, with FOLFIRI causing more mucositis and nausea/vomiting, while FOLFOX6 was associated with higher rates of neutropenia and neurosensory toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. Tournigand, C., André, T., Achille, E., et al.[2023]

In a study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

In a study of 66 patients with chemotherapy-refractory metastatic colorectal cancer, the combination of cetuximab with bevacizumab and mFOLFOX6 showed manageable safety, but significant toxicity led to a high discontinuation rate, with 56% of patients stopping treatment before disease progression.

Despite not causing excessive life-threatening toxicity, the addition of cetuximab resulted in a notable number of patients experiencing severe side effects, prompting the conclusion that this combination therapy should not be used together for treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. Ocean, AJ., Polite, B., Christos, P., et al.[2021]

In a phase II study involving 46 patients with advanced colorectal cancer resistant to previous treatments, the FOLFOX2 regimen (oxaliplatin, leucovorin, and 5-FU) achieved a high overall response rate of 46%, including one complete response and 20 partial responses.

The treatment was associated with manageable toxicities, primarily neutropenia (39%) and peripheral neuropathy (9%), indicating that while the regimen is effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. de Gramont, A., Vignoud, J., Tournigand, C., et al.[2019]

The FOLFOX regimen, which combines Leucovorin and fluorouracil with oxaliplatin, is a standard first-line treatment for metastatic colorectal cancer, but it has significant side effects including neutropenia and sensory neuropathy.

Immediate hypersensitivity reactions, such as anaphylaxis, can occur in up to 0.6% of patients receiving FOLFOX, highlighting the importance of monitoring for adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[FOLFOX]. Mishima, H., Ikenaga, M., Tsujinaka, T., et al.[2013]

S-1, an oral chemotherapy drug combining tegafur with modulators, has shown advantages over standard 5-FU-based treatments for gastric cancer in large Phase III studies, making it a recommended option in treatment guidelines.

S-1, either alone or in combination with cisplatin, is non-inferior to traditional 5-FU regimens while offering greater convenience and reduced toxicity, highlighting its potential for higher efficacy in treating gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. Satoh, T., Sakata, Y.[2022]

The combination of oral doxifluridine (d-FUR) and l-leucovorin showed some efficacy in treating gastric cancer, with a 15% objective response rate in a study of 50 patients, primarily those previously treated with 5-FU.

While the treatment was well tolerated with moderate toxicity, including 14% experiencing severe diarrhea, the results for pancreatic cancer were less promising, with only a 4% response rate, consistent with existing literature on fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxifluridine as palliative treatment in advanced gastric and pancreatic cancer patients. Di Bartolomeo, M., Bajetta, E., Somma, L., et al.[2018]

In a study involving 508 patients with untreated metastatic colorectal cancer, the combination of FOLFOXIRI and bevacizumab significantly improved progression-free survival (12.1 months) compared to FOLFIRI and bevacizumab (9.7 months), indicating enhanced treatment efficacy.

While FOLFOXIRI plus bevacizumab showed better outcomes, it also resulted in higher rates of severe side effects, such as neurotoxicity and diarrhea, highlighting the need to balance treatment benefits with potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. Loupakis, F., Cremolini, C., Masi, G., et al.[2022]

New agents like irinotecan (CPT-11) and oxaliplatin have shown promising efficacy in treating colorectal carcinoma (CRC), especially for patients resistant to standard therapies like 5-fluorouracil (5-FU) and leucovorin.

Combination therapies involving 5-FU with newer agents such as trimetrexate, capecitabine, and S-1 are showing encouraging response rates, suggesting potential changes in the standard treatment protocols for advanced CRC in the near future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs in the treatment of colorectal carcinoma. Punt, CJ.[2019]

References

1. France pubmed.ncbi.nlm.nih.gov

[Reflexion on a good strategy of use of oxaliplatine with 5-fluorouracil and its derivatives in patients with advanced colorectal cancer]. [2018]

2. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of fluorouracil, leucovorin plus oxaliplatin (FOLFOX4 and modified FOLFOX6) followed by fluorouracil, leucovorin plus irinotecan(FOLFIRI)for advanced or metastatic colorectal cancer--case studies. [2016]

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

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. [2023]

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

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. [2021]

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

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. [2019]

8. Japan pubmed.ncbi.nlm.nih.gov

[FOLFOX]. [2013]

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

S-1 for the treatment of gastrointestinal cancer. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Doxifluridine as palliative treatment in advanced gastric and pancreatic cancer patients. [2018]

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

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. [2022]

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

New drugs in the treatment of colorectal carcinoma. [2019]