Nivolumab + FOLFOX + Regorafenib for Esophageal Cancer

Recruiting at 6 trial locations

Overseen By Yelena Janjigian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Anti-PD-1 agents

Disqualifiers: HER2-positive, Autoimmune disorders, CNS metastases, 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: 4

Duration: Until disease progression or unacceptable toxicity

39 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on systemic steroid therapy or any form of immunosuppressive therapy, you must stop these at least 7 days before starting the trial treatment.

What data supports the effectiveness of the drug combination Nivolumab, FOLFOX, and Regorafenib for esophageal cancer?

Research shows that adding Nivolumab to chemotherapy can improve survival in advanced esophageal and related cancers, and the combination of Nivolumab with oxaliplatin-based chemotherapy has shown a sustained antitumor effect. Additionally, the FOLFOX regimen has been effective in treating inoperable or metastatic esophageal cancer, with a response rate of 62.9% on the primary tumor. ^{1 2 3 4 5}

Is the combination of Nivolumab, FOLFOX, and Regorafenib generally safe for humans?

Regorafenib, used in various cancers, has a manageable safety profile with common side effects like skin reactions, high blood pressure, fatigue, diarrhea, and liver issues. These side effects are usually mild to moderate and can be managed with dose adjustments and supportive care. Nivolumab, when combined with chemotherapy, has been studied for safety in advanced esophageal and related cancers, but specific safety data for this exact combination in esophageal cancer is limited. ^{1 6 7 8 9}

How is the drug combination of Nivolumab, FOLFOX, and Regorafenib unique for treating esophageal cancer?

This drug combination is unique because it combines Nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with FOLFOX chemotherapy and Regorafenib, a drug that targets multiple pathways involved in cancer growth. This approach aims to enhance the overall antitumor effect, especially in cases where standard treatments are limited. ^{1 2 9 10 11}

What is the purpose of this trial?

The purpose of this study is to find out whether combining nivolumab, FOLFOX, and regorafenib may be a safe and effective treatment for people who have HER2-negative metastatic esophagogastric cancer. Nivolumab is an antibody, like the proteins made by the immune system to protect the body from harm. Nivolumab blocks the protein PD-1 (programmed cell death receptor-1) that usually acts as a "brake" on the immune system. Blocking this protein is like releasing the brakes, so that the immune system can target cancer cells and destroy them. FOLFOX is a combination of three standard chemotherapy drugs (leucovorin, 5-fluorouracil, and oxaliplatin) commonly used to treat your type of cancer. The drugs work by damaging the DNA in cancer cells, which can cause the cells to stop growing and die. Regorafenib is a type of drug called a tyrosine kinase inhibitor (TKI). This drug targets the tyrosine kinase protein found in or on the surface of cancer cells that the cells need to survive and grow. Blocking this protein may stop cancer cells from growing, or cause them to grow more slowly or to shrink. The study researchers think that combining nivolumab, FOLFOX, and regorafenib may be a more effective treatment for HER2-negative metastatic esophagogastric cancer than the usual chemotherapy treatment(s) alone.

Research Team

Yelena Janjigian, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with HER2-negative metastatic esophagogastric cancer can join this trial. They should have adequate organ function, no severe neuropathy, and their disease must be visible on scans. Excluded are those with HER2-positive cancer, difficulty swallowing pills, recent major surgery or radiation, prior regorafenib treatment, certain autoimmune diseases unless specified exceptions apply, active infections like HIV or hepatitis B/C, uncontrolled heart conditions or blood pressure issues.

Inclusion Criteria

AST and ALT ≤2.5X ULN

Absolute neutrophil count ≥1500/mcL

Platelets ≥100,000/mcL

Exclusion Criteria

Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of trial treatment

You are unable to swallow pills.

You have already received treatment with regorafenib.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive induction therapy with regorafenib and nivolumab

4 weeks

2 visits (in-person)

Treatment

Participants receive nivolumab, FOLFOX, and regorafenib in 28-day cycles

Until disease progression or unacceptable toxicity

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• FOLFOX chemotherapy with oxaliplatin
• Nivolumab
• Regorafenib

Trial Overview The study is testing a combination of nivolumab (an immune system booster), FOLFOX chemotherapy (a DNA-damaging drug trio), and regorafenib (a growth-blocking drug) to see if they work better together than standard treatments for advanced stomach cancers that don't respond to HER2-targeted therapies.

Participant Groups

Group I: Nivolumab Combined With FOLFOX and Regorafenib Experimental Treatment 3 Interventions

Each treatment cycle consists of 28 days. Patients will initially receive induction therapy with regorafenib (80 mg on days 1-21 of the 28-day cycle) and nivolumab (240 mg on days 1 and 15 of the 28-day cycle). Starting on cycle 2, day 1, patients will also receive FOLFOX chemotherapy with oxaliplatin (85 mg/m2 IV), leucovorin (400 mg/m2 IV), 5-FU (400 mg/m2 IV bolus), and 5-FU (2400 mg/m2/day continuous IV infusion over 48 h). If the patient is not a good candidate for induction regorafenib and nivolumab (i.e. symptomatic from a large burden of disease), 5-FU and oxaliplatin can be added during cycle 1 at the treating physician's discretion. 39 Patients will continue with this regimen until disease progression, unacceptable toxicity, or development of serious intercurrent illness. Treatment will be performed on the scheduled day (±7-day treatment window).

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

In a phase 2 trial involving 39 patients with advanced HER2-negative oesophagogastric adenocarcinoma, the combination of regorafenib, nivolumab, and chemotherapy resulted in 71% of patients being progression-free at 6 months, indicating promising efficacy.

The treatment was generally safe, with the most common adverse effects being fatigue and decreased neutrophil count, and no treatment-related deaths reported, suggesting that this combination could be a viable option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. Cytryn, SL., Moy, RH., Cowzer, D., et al.[2023]

Pre-operative chemotherapy with Paclitaxel-Carboplatin followed by adjuvant immunotherapy using Nivolumab has significantly improved the management of locally advanced esophageal cancer, which historically has a poor prognosis.

Current trials are exploring the effectiveness of immunotherapy for non-operable esophageal cancers, while strategies like dose escalation and combining pre-operative chemo-radiotherapy with trastuzumab have not shown benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. Quéro, L., Besnard, C., Guillerm, S., et al.[2022]

The combination of neoadjuvant 5-fluorouracil, oxaliplatin, and lapatinib with radiation therapy is safe for patients with localized HER2-positive esophagogastric adenocarcinoma, as shown in a nonrandomized trial with 12 participants.

The pathologic complete response (pCR) rate was 8%, indicating some effectiveness, but the study was limited by low patient enrollment, suggesting that further evaluation in a larger group is needed to better assess efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas. Shepard, G., Arrowsmith, ER., Murphy, P., et al.[2018]

Regorafenib is the first approved tyrosine kinase inhibitor for metastatic colorectal cancer, showing significant improvements in progression-free and overall survival in patients who had previously undergone multiple lines of chemotherapy and targeted therapies, based on results from two phase III trials.

While regorafenib has a safety profile similar to other tyrosine kinase inhibitors, it is associated with specific adverse events like hand-foot skin reaction and hypertension, which can be managed effectively through patient education and timely dose adjustments, allowing patients to continue benefiting from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Hofheinz, RD., Arnold, D., Kubicka, S., et al.[2015]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

In a study of 72 patients with microsatellite stable metastatic colorectal cancer, regorafenib or fruquintinib combined with sintilimab showed a median progression-free survival of 4.2 months and an overall survival of 10.5 months, indicating these combinations are viable third-line treatment options.

The treatment was generally well-tolerated, with only 15.3% of patients experiencing severe adverse events, and patients without liver metastasis showed better response rates and overall survival, suggesting they may benefit more from this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. Nie, C., Lv, H., Chen, B., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. [2022]

3. France pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer. [2018]

5. England pubmed.ncbi.nlm.nih.gov

A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. [2015]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. [2022]

10. England pubmed.ncbi.nlm.nih.gov

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). [2023]

11. England pubmed.ncbi.nlm.nih.gov

First-line treatment of unresectable or metastatic HER2 positive esophagogastric adenocarcinoma: liquid biomarker analysis of the phase 2 INTEGA trial. [2023]