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A Study of Nivolumab Combined with FOLFOX and Regorafenib in Patients Who Have HER2-Negative Metastatic Esophagogastric Cancer

Trial Status: Active

This phase II trial studies the effect of nivolumab, combination chemotherapy, and regorafenib in treating patients with HER2-negative esophagus or stomach (esophagogastric) cancer that has spread beyond its original location to other parts of the body (metastatic). 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. 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. FOLFOX is a combination of three standard chemotherapy drugs (leucovorin, 5-fluorouracil, and oxaliplatin) that work by damaging the DNA in cancer cells, which can cause the cells to stop growing and die. Giving nivolumab and regorafenib together with combination chemotherapy may work better than combination chemotherapy alone in treating patients with esophagus or stomach cancer.

Inclusion Criteria

  • Patients must have histologically or cytologically confirmed metastatic esophageal, gastric, or gastroesophageal junction adenocarcinoma
  • Patients must have disease that can be evaluated radiographically within 28 days of the start of study treatment. This may be measurable disease or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Age 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
  • Peripheral neuropathy grade =< 1
  • Available archival tissue for correlative analysis (biopsy is required if no archival tissue is available)
  • Absolute neutrophil count >= 1500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN)
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN, except patients with Gilbert’s disease (=< 3 x ULN)
  • Aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Albumin >= 3 mg/dL

Exclusion Criteria

  • Confirmed HER2-positive disease (IHC 3+ or 2+, fluorescence in situ hybridization HER2:CEP17 ratio >= 2)
  • Inability to swallow oral pills
  • Prior chemotherapy for metastatic disease. Patients with metastatic disease after treatment for localized esophagogastric cancer may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if > 6 months have elapsed between the end of adjuvant therapy and registration
  • Currently participating in a study and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Underwent major surgical procedure within 4 weeks of registration
  • Underwent radiation within 2 weeks of registration
  • Received prior therapy with regorafenib
  • Received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent
  • 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
  • A known history of active Bacillus tuberculosis
  • A known active central nervous system metastases and/or carcinomatous meningitis
  • A known history of or any evidence of active, noninfectious pneumonitis
  • An active infection requiring systemic therapy
  • An active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, systemic lupus erythematosus, Wegener syndrome [granulomatosis with polyangiitis], myasthenia gravis, Grave’s disease, rheumatoid arthritis, hypophysitis, uveitis) within the 3 years before the start of treatment. The following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
  • A known history of human immunodeficiency virus (HIV 1/2 antibodies)
  • Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Received a live vaccine within 30 days of planned start of study therapy
  • Active or clinically significant cardiac disease, including congestive heart failure–New York Heart Association class > II, active coronary artery disease, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, unstable angina (anginal symptoms at rest), new-onset angina within 3 months before initiation, or myocardial infarction within 6 months before initiation
  • Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management
  • Evidence or history of bleeding diathesis or coagulopathy
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 120 days after the last dose of trial treatment
  • Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186

New York

Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Yelena Y. Janjigian
Phone: 646-888-4186


I. Determine the efficacy of nivolumab in combination with fluorouracil, leucovorin calcium, oxaliplatin (FOLFOX) and regorafenib in patients with previously untreated metastatic esophagogastric cancer, as measured by 6- month progression free survival (PFS).


I. Establish the safety of nivolumab in combination with FOLFOX and regorafenib in patients with metastatic esophagogastric cancer.

II. Determine the overall response rate (ORR; defined as complete response [CR] + partial response [PR]) and the clinical benefit (defined as stable disease [SD] + CR + PR).

III. Observe other measures of efficacy, including median PFS and overall survival (OS) (median, 1-year).


I. Collect archival tumor samples for correlative analysis, including but not limited to immunohistochemical (IHC) analysis and targeted next-generation sequencing (NGS; MSK-IMPACT) to identify genomic alterations and tumor mutational burden (TMB).

II. Explore PD-L1 expression as measured by combined positive score (CPS) as a predictive biomarker.

III. Use circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and peripheral blood mononuclear cells (PBMCs) collected during the course of the study to explore the mechanisms of primary and acquired resistance to FOLFOX, nivolumab, and regorafenib and the relationship of these mechanisms to response, PFS, and OS.

IV. Bank tumor and blood material at screening and postprogression for future correlative analysis, including but not limited to whole-exome analysis to determine the mutation load and specific neoantigen landscape.

V. Explore the activity of induction regorafenib and nivolumab in patients with metastatic esophagogastric cancer.

VI. Use patient biopsy specimens to generate patient-derived organoids (PDOs).

VII. Estimate median PFS and OS in patients who received induction regorafenib and nivolumab.


Patients receive nivolumab intravenously (IV) over 30 minutes on days 1 and 15 and regorafenib orally (PO) once daily (QD) on days 1-21. Beginning cycle 2, patients also receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 48 hours on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Yelena Y. Janjigian

  • Primary ID 20-540
  • Secondary IDs NCI-2021-01523
  • ID NCT04757363