Chemotherapy + Immunotherapy for Esophageal and Gastric Cancer

Recruiting at 831 trial locations

Overseen By Aishwarya Vijendran

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Pregnancy, Gilbert's syndrome, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 3 years

382 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for advanced esophageal and gastric cancer that cannot be surgically removed or has spread. It compares two chemotherapy combinations: one with mFOLFIRINOX (which includes irinotecan) and one with mFOLFOX, both often combined with the immunotherapy drug nivolumab (Opdivo). The researchers aim to determine if adding irinotecan can shrink tumors more effectively and extend patient survival. This trial may suit individuals with advanced, HER2-negative cancer in the esophagus, gastroesophageal junction, or stomach who have not received prior treatment for metastatic disease. As a Phase 3 trial, it represents the final step before FDA approval, offering patients early access to potentially effective treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on medications like corticosteroids or other immunosuppressive drugs, you may need to adjust them as per the trial's requirements.

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

A previous study showed that the combination of mFOLFIRINOX, with or without nivolumab, shrank tumors in patients with advanced gastroesophageal cancers. However, this treatment can have side effects. Although the study did not list these side effects, testing at a later stage indicates some safety in earlier trials.

For mFOLFOX with nivolumab, research from the CheckMate 649 trial demonstrated that this combination extended patients' lives. The side effects were manageable, allowing doctors to address most of them. No severe side effects prevented dose increases.

Both treatments have been tested with nivolumab, an immunotherapy drug that aids the immune system in fighting cancer cells. Previous studies found these treatments to be relatively well-tolerated. However, like most cancer treatments, they can have side effects, so discussing these with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine chemotherapy with immunotherapy, offering a fresh approach to tackling esophageal and gastric cancer. Unlike traditional chemotherapy alone, these treatments add nivolumab, an immunotherapy drug, which helps the immune system better recognize and attack cancer cells. The arm groups differ slightly; Arm I uses mFOLFIRINOX, which includes irinotecan for a broader attack on cancer cells, while Arm II uses mFOLFOX, skipping irinotecan for a potentially different side effect profile. This combination aims to improve effectiveness and patient outcomes, making it a promising development in cancer treatment.

What evidence suggests that this trial's treatments could be effective for esophageal and gastric cancer?

Research has shown that combining mFOLFIRINOX with nivolumab, which participants in this trial may receive, may shrink tumors more effectively than mFOLFOX with nivolumab, another treatment option in this trial, for people with advanced gastroesophageal cancers. The mFOLFIRINOX treatment includes irinotecan, which stops cancer cells from dividing, potentially killing more tumor cells. Studies have also found that nivolumab, a type of immunotherapy, can help patients live longer when used with chemotherapy. In a three-year follow-up, patients who received nivolumab with chemotherapy had better survival rates than those who had chemotherapy alone. This suggests that nivolumab boosts the effectiveness of chemotherapy in treating these cancers. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

Adults with advanced, inoperable or metastatic HER2 negative esophageal, gastroesophageal junction, and gastric adenocarcinoma can join. They shouldn't have had previous treatment for their advanced cancer but may have had prior therapy if completed over a year ago. Participants need adequate organ function and no active autoimmune diseases requiring recent treatment. Those with certain heart conditions or infections like HIV must meet specific criteria.

Inclusion Criteria

Total bilirubin =< 1.5 x ULN

HIV positive patients meeting specific criteria

Measurable disease or non-measurable but evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Exclusion Criteria

I am of childbearing age and have a negative pregnancy test.

No medical conditions making the protocol unreasonably hazardous

Not pregnant and not nursing

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive mFOLFIRINOX or mFOLFOX with nivolumab as clinically indicated, with MRI and CT scans throughout the trial

Up to 3 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• mFOLFIRINOX
• mFOLFOX
• Nivolumab

Trial Overview

The trial compares mFOLFIRINOX (a combination of chemotherapy drugs) to mFOLFOX (another chemo combo), both aiming to stop tumor growth by killing cells or preventing cell division. Some patients will also receive Nivolumab, an immunotherapy drug designed to boost the immune system's response against cancer cells.

How Is the Trial Designed?

Group I: Arm I (mFOLFIRINOX, nivolumab) Experimental Treatment 9 Interventions

Patients receive fluorouracil IV, leucovorin calcium IV, oxaliplatin IV, and irinotecan IV on study and nivolumab IV as clinically indicated. Patients undergo MRI and a CT scan throughout the trial. Patients may also undergo blood sample collection on study.

Group II: Arm II (mFOLFOX, nivolumab) Active Control 8 Interventions

Patients receive fluorouracil IV, leucovorin calcium IV, and oxaliplatin IV on study and nivolumab IV as clinically indicated. Patients undergo MRI and a CT scan throughout the trial. Patients may also undergo blood sample collection on study.

mFOLFIRINOX is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as mFOLFIRINOX for:

• Pancreatic ductal adenocarcinoma (PDAC)

Approved in United States as mFOLFIRINOX for:

• Advanced pancreatic cancer

Approved in Canada as mFOLFIRINOX for:

• Resectable pancreatic ductal adenocarcinoma

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 242 patients with metastatic esophagus cancer, 38.8% received second-line treatment with the modified FOLFOX6 (mFOLFOX6) regimen after failing cisplatin-plus-5-fluorouracil chemotherapy, showing an objective response rate of 41.4%.

While mFOLFOX6 was effective, with 6.3% achieving complete response and 35.1% achieving partial response, it also had a high incidence of grade 3/4 toxicity in 71.2% of patients, primarily due to hematologic issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-Line Modified FOLFOX6 Regimen in The Patients with Metastatic Esophagus Cancer. Koca, D., Ozdemir, O., Demir, D., et al.[2018]

5-Fluorouracil (5-FU) combined with folinic acid (FA) or alpha-interferon (IFN) has shown improved clinical activity in treating esophageal and gastric cancers compared to 5-FU alone, with 27% objective remissions reported in esophageal cancer.

In advanced gastric cancer, the combination of 5-FU/FA and 5-FU/IFN resulted in higher remission rates, with some studies reporting response rates exceeding 50% when combined with other chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical modulation of 5-fluorouracil by folinic acid or alpha-interferon with and without other cytostatic drugs in gastric, esophageal, and pancreatic cancer. Wilke, H., Stahl, M., Schmoll, HJ., et al.[2018]

In a study of 30 patients with resectable esophageal squamous cell carcinoma, a chemotherapy regimen combining 5-fluorouracil, cisplatin, and interferon-alpha showed promising results, with a median overall survival of 26.3 months.

The treatment led to a complete pathological response in 4 out of 23 patients who underwent esophagectomy, indicating significant effectiveness, although there was one toxic death due to esophageal perforation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. Bazarbashi, S., Abdelsalam, M., Amin, T., et al.[2013]

A patient with esophageal cancer and colon cancer was treated with a modified FOLFOX6 chemotherapy regimen combined with radiotherapy, resulting in a partial response of the esophageal tumor and effective control of the disease.

Despite experiencing grade 3 leukopenia, the modified FOLFOX6 regimen was generally well tolerated, suggesting it could be a viable treatment option for inoperable esophageal cancer, warranting further clinical trials in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A case of esophageal cancer associated with colon cancer successfully treated with combination chemotherapy of FOLFOX and concurrent radiotherapy]. Watanabe, Y., Tsutsui, M., Takeda, S., et al.[2013]

The ECF regimen (epirubicin, cisplatin, and protracted venous infusion fluorouracil) showed a significantly higher overall response rate of 45% compared to 21% for the FAMTX regimen (5-FU, doxorubicin, and methotrexate) in a study of 274 patients with advanced esophagogastric cancer.

Patients treated with ECF had a median survival of 8.9 months, which was longer than the 5.7 months observed with FAMTX, along with better quality of life scores at 24 weeks, indicating that ECF is a more effective and tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. Webb, A., Cunningham, D., Scarffe, JH., et al.[2022]

The modified FOLFOXIRI regimen combined with α (mFOLFOXIRI+α) showed promising efficacy in treating advanced and recurrent colorectal cancer (ARCC), with a median progression-free survival (PFS) of 565 days and a response rate (RR) of 66.7%, compared to 322 days and 31.3% in other treatment regimens.

Despite a higher incidence of grade ≥3 leukopenia (58%), mFOLFOXIRI+α had a relatively low rate of febrile neutropenia (17%), indicating a manageable safety profile while effectively alleviating symptoms related to tumor burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Modified FOLFOXIRI+α in the Treatment of Advanced and Recurrent Colorectal Cancer: A Single-center Experience. Kobayashi, K., Yamaguchi, S., Ito, S., et al.[2023]

In a study of 69 Asian patients with metastatic colorectal cancer, the combination of FOLFOXIRI and bevacizumab resulted in a high progression-free survival (PFS) rate of 75.2% at 10 months, indicating its effectiveness as a first-line treatment.

However, this regimen was associated with significant adverse events, particularly high rates of neutropenia (72.5%) and hypertension (34.8%), highlighting the need for careful monitoring, especially in patients with specific UGT1A1 genetic polymorphisms that increase the risk of severe neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. Oki, E., Kato, T., Bando, H., et al.[2022]

Modified-dose FOLFIRINOX (mFOLFIRINOX) demonstrated comparable efficacy to standard-dose FOLFIRINOX (sFOLFIRINOX) in treating pancreatic cancer, with similar objective response rates and overall survival outcomes among 130 patients studied.

mFOLFIRINOX was associated with significantly lower rates of severe adverse events, such as neutropenia, anorexia, and diarrhea, suggesting it is a safer option for patients who may be concerned about toxicity while maintaining effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and safety between standard-dose and modified-dose FOLFIRINOX as a first-line treatment of pancreatic cancer. Kang, H., Jo, JH., Lee, HS., et al.[2022]

The modified FOLFIRINOX (mFOLFIRINOX) regimen showed a tolerable safety profile with lower hematological toxicity compared to the full-dose FOLFIRINOX, while still maintaining comparable efficacy in treating advanced pancreatic ductal adenocarcinoma (PDAC).

In a study of 18 patients, 80% achieved at least stable disease, with a median overall survival of 9.3 months and progression-free survival of 7.2 months, indicating that mFOLFIRINOX can be an effective treatment option for fit patients with advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. Ghorani, E., Wong, HH., Hewitt, C., et al.[2023]

The modified FOLFOX-6 (mFOLFOX-6) regimen shows promise for treating gastric cancer patients with gastrointestinal obstructions, with a median overall survival of 8.0 months based on a retrospective analysis of 18 patients.

Out of the 18 patients treated, 13 experienced improved oral intake, allowing 12 of them to continue treatment as outpatients, indicating potential benefits in quality of life alongside survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of modified FOLFOX-6 for patients with gastric cancer and a gastrointestinal obstruction. Yukami, H., Terazawa, T., Goto, M., et al.[2020]

The modified 5-fluorouracil/leucovorin/irinotecan (mFOLFIRI) regimen showed a response rate of 29.7% and a clinical benefit rate of 57.2% in 91 patients with advanced gastric cancer, indicating its efficacy as a second-line treatment.

Despite its effectiveness, the mFOLFIRI regimen was associated with significant adverse events, including neutropenia in 18.7% of patients, highlighting the need for careful monitoring and potential dose modifications during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers. Ramaswamy, A., Ostwal, V., Gupta, K., et al.[2022]

The modified FOLFOX6 (mFOLFOX6) regimen was found to be an effective and tolerable neoadjuvant chemotherapy for gastric cancer, with a 45.8% radiological response rate and a 49.2% rate of significant histological regression in patients undergoing surgery.

The ypTNM stage and the degree of histological regression (GHR) were identified as important prognostic factors for overall survival, suggesting that GHR could help guide postoperative chemotherapy decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of a modified FOLFOX6 regimen as neoadjuvant chemotherapy for locally advanced gastric cancer. Wang, X., Zhao, L., Liu, H., et al.[2022]

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