Chemotherapy + Immunotherapy for Esophageal and Gastric Cancer

Recruiting in Palo Alto (17 mi)

+774 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Pregnancy, Gilbert's syndrome, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase III trial compares the effect of modified fluorouracil, leucovorin calcium, oxaliplatin, and irinotecan (mFOLFIRINOX) to modified fluorouracil, leucovorin calcium, and oxaliplatin (mFOLFOX) for the treatment of advanced, unresectable, or metastatic HER2 negative esophageal, gastroesophageal junction, and gastric adenocarcinoma. The usual approach for patients is treatment with FOLFOX chemotherapy. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fluorouracil stops cells from making DNA and it may kill tumor cells. Leucovorin is used with fluorouracil to enhance the effects of the drug. Oxaliplatin works by killing, stopping, or slowing the growth of tumor cells. Some patients also receive an immunotherapy drug, nivolumab, in addition to FOLFOX chemotherapy. Immunotherapy may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill tumor cells. Adding irinotecan to the FOLFOX regimen could shrink the cancer and extend the life of patients with advanced gastroesophageal cancers.

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.

What data supports the effectiveness of the drug combination mFOLFIRINOX, FOLFIRINOX, mFOLFOX, Nivolumab, and Opdivo for esophageal and gastric cancer?

Research shows that modified FOLFOX6 (mFOLFOX6) has been effective as a second-line treatment for metastatic esophageal cancer, and combinations of 5-fluorouracil (5-FU) with other drugs have shown promise in treating gastrointestinal cancers, including esophageal and gastric cancers. Additionally, FOLFOX combined with radiotherapy has been effective for inoperable esophageal cancer. ^{1 2 3 4 5}

Is the combination of chemotherapy and immunotherapy safe for treating esophageal and gastric cancer?

The modified FOLFIRINOX and FOLFOX regimens, which are similar to the treatment being considered, have been studied for other cancers like pancreatic and colorectal cancer. These treatments can cause side effects, such as low white blood cell counts and fever, but they are generally considered safe when managed properly. ^{6 7 8 9 10}

How is the mFOLFIRINOX treatment different from other drugs for esophageal and gastric cancer?

The mFOLFIRINOX treatment combines chemotherapy with immunotherapy, which is unique because it uses a modified version of the FOLFIRINOX regimen, typically used for other cancers, to potentially enhance effectiveness in esophageal and gastric cancer. This approach may offer an alternative for patients who cannot tolerate standard oral treatments due to conditions like gastrointestinal obstructions. ^{1 3 4 11 12}

Research Team

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• mFOLFIRINOX (Chemotherapy)
• mFOLFOX (Chemotherapy)
• Nivolumab (Checkpoint Inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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+

Suzanne George

Alliance for Clinical Trials in Oncology

Chief Medical Officer since 2015

MD from Harvard Medical School

Evanthia Galanis

Alliance for Clinical Trials in Oncology

Chief Executive Officer since 2022

MD from Mayo Clinic

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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 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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Second-Line Modified FOLFOX6 Regimen in The Patients with Metastatic Esophagus Cancer. [2018]

2. United States 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. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. [2013]

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

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

[A case of esophageal cancer associated with colon cancer successfully treated with combination chemotherapy of FOLFOX and concurrent radiotherapy]. [2013]

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

A phase II study of a modified FOLFOX6 regimen as neoadjuvant chemotherapy for locally advanced gastric cancer. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. [2023]

8. United States 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. [2022]

9. Japan 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. [2023]

10. China 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. [2022]

11. Australia pubmed.ncbi.nlm.nih.gov

Impact of modified FOLFOX-6 for patients with gastric cancer and a gastrointestinal obstruction. [2020]

12. India pubmed.ncbi.nlm.nih.gov

Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers. [2022]