Nivolumab + FOLFOX + Regorafenib for Esophageal Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of three treatments—nivolumab, FOLFOX, and regorafenib—can safely and effectively treat HER2-negative metastatic esophagogastric cancer. Nivolumab boosts the immune system to attack cancer cells, FOLFOX consists of chemotherapy drugs that halt cancer cell growth, and regorafenib, a targeted therapy, blocks proteins that aid cancer cell survival. The trial seeks participants with HER2-negative metastatic esophageal, gastric, or gastroesophageal junction cancer who have not received chemotherapy for their metastatic disease and can take oral medication. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that the combination of nivolumab, FOLFOX, and regorafenib has been tested for safety in people with advanced esophagogastric cancer. Studies suggest this combination is generally safe and effective for patients.

Nivolumab is usually well-tolerated, with some experiencing side effects like tiredness or skin reactions. FOLFOX, a type of chemotherapy, might cause nausea or lower blood cell counts, which are common with chemotherapy. Regorafenib, another cancer drug, can cause side effects such as tiredness, diarrhea, or high blood pressure.

While these treatments can have side effects, they are generally considered manageable. This suggests the benefits of using these drugs together might outweigh the risks for many patients. Discussing any concerns with a healthcare provider is important to understand how this treatment might work for an individual. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Nivolumab, FOLFOX chemotherapy, and Regorafenib for esophageal cancer because it introduces an innovative approach compared to standard treatments like chemotherapy and radiation. Unlike traditional methods, Nivolumab is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. Regorafenib adds another layer by inhibiting certain proteins that tumors need to grow and spread. This multi-pronged strategy not only aims to target the cancer directly but also enhances the body's natural defenses, potentially leading to improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for HER2-negative metastatic esophagogastric cancer?

Research has shown that combining nivolumab with chemotherapy can extend the lives of patients with advanced esophagogastric cancer. In this trial, participants will receive a combination of nivolumab, FOLFOX chemotherapy, and regorafenib. Nivolumab aids the immune system in attacking cancer cells. FOLFOX, a common chemotherapy treatment, halts cancer cell growth by damaging their DNA. Regorafenib blocks proteins that promote cancer cell growth. Early results suggest that these treatments together might be more effective than chemotherapy alone for patients with HER2-negative metastatic esophagogastric cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Yelena Janjigian, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04757363

A Study of Nivolumab Combined With FOLFOX and ... The study researchers think that combining nivolumab, FOLFOX, and regorafenib may be a more effective treatment for HER2-negative metastatic esophagogastric ...

2. researchgate.net researchgate.net/publication/358268285_INTEGRATE_IIb_A_randomized_phase_III_open_label_study_of_regorafenib_nivolumab_versus_standard_chemotherapy_in_refractory_advanced_gastroesophageal_cancer_AGOC

INTEGRATE IIb: A randomized phase III open label study of ... INTEGRATE IIb–will compare the effectiveness of the combination of regorafenib & nivolumab in pre-treated patients with AGOC to current standard chemotherapy.

3. clinicaltrial.be clinicaltrial.be/fr/details/47484?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

A Study of Nivolumab Combined With FOLFOX and ... The study researchers think that combining nivolumab, FOLFOX, and regorafenib may be a more effective treatment for HER2-negative metastatic ...

4. targetedonc.com targetedonc.com/view/5-year-update-sustains-nivolumab-chemo-efficacy-in-frontline-gastric-gej-esophageal-cancer

5-Year Update Sustains Nivolumab/Chemo Efficacy in ... The first-line combination of nivolumab (Opdivo) and chemotherapy continued to show deep responses and an overall survival (OS) benefit vs chemotherapy alone.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11208000/

First-line regorafenib with nivolumab and chemotherapy in ... The addition of nivolumab to chemotherapy improves survival in patients with advanced esophagogastric (esophageal, gastric, or gastroesophageal junction) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05394740

Clinical Study of Regorafenib and Nivolumab Plus ... This is an open-label, single-arm, single-center Phase Ib/II study to exploratorily evaluate the tolerability, safety, and efficacy of regorafenib and nivolumab ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK603609/table/tr82698680670259_ch02_t14/?report=objectonly

Table 14, Summary of Key Model Parameters - Nivolumab ... Table 14Summary of Key Model Parameters ; Annual incidence of esophageal cancer · Proportion of esophageal cancer patients with esophageal adenocarcinoma ; 0.0057%.