Combination of chemotherapy and immunotherapy for advanced esophageal and gastric cancer

Phase 2 Trial of 5-Fluorouracil, Oxaliplatin and Liposomal Irinotecan and Immunotherapy (Plus Trastuzumab for HER2-positive Disease) During 1st Line Treatment of Advanced Esophageal and Gastric Adenocarcinoma

This study is testing a new combination of chemotherapy and immunotherapy to see if it helps people with advanced esophageal and gastric cancer feel better and have fewer side effects than current treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 52 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Wisconsin, Madison (Academic / other)
• Drugs / interventions: nivolumab, pembrolizumab, chemotherapy, immunotherapy, prednisone, trastuzumab
• Locations: 1 site (Madison, Wisconsin)
• Trial ID: NCT04150640 on ClinicalTrials.gov

What this trial studies

This open-label, phase II trial evaluates the safety and efficacy of a combination treatment involving 5-FU, oxaliplatin, nal-IRI, and immunotherapy (trastuzumab for HER2-positive tumors) as a first-line therapy for patients with advanced esophageal and gastric adenocarcinoma. Participants will be divided into four cohorts based on their HER2 status, receiving different combinations of the drugs. The study aims to determine if this new combination is better tolerated than existing chemotherapy regimens. The trial will assess the response rates and safety profiles of these treatments in a multi-site setting.

Who should consider this trial

Good fit: Ideal candidates include individuals with locally advanced or metastatic esophageal or gastric adenocarcinoma who have not received prior systemic therapy for advanced disease.

Not a fit: Patients with prior systemic therapy for advanced disease or those with significant comorbidities affecting their ability to tolerate treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a more tolerable and effective first-line therapy option for patients with advanced esophageal and gastric adenocarcinoma.

How similar studies have performed: Other studies have shown promising results with similar combinations of chemotherapy and immunotherapy, suggesting potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information.

NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
* Histological or cytological confirmed locally advanced or metastatic EGA. Known HER2 status prior to treatment initiation required. Known PDL1 CPS status prior to treatment initiation.
* Measurable disease according to RECIST v1.1.
* No prior lines of systemic therapy for advanced disease.
* Participants who had received neoadjuvant or adjuvant therapy or definitive chemoradiation will be allowed to participate if recurrence occurred 6 months or longer from the completion of all prior treatments.
* Demonstrate adequate organ function as defined below; all screening labs to be obtained within 14 days prior to registration

  * Absolute Neutrophil Count (ANC) ≥1,500 /μl without the use of hematopoietic growth factors
  * Hemoglobin (Hgb) ≥8 g/dL (blood transfusions are permitted for participants with hemoglobin levels below 8 g/dL)
  * Platelets ≥100,000 /μl
  * Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl). CrCl calculation using the Cockcroft-Gault formula. ≥50 mL/min for participants with creatinine levels \> 1.5 X institutional ULN
  * Bilirubin within normal range for the institution (biliary drainage is allowed for biliary obstruction)
  * Aspartate aminotransferase (AST) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  * Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  * Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Women of childbearing potential should have a negative urine or serum pregnancy test within 14 days of study registration. NOTE: Women are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
* Women of childbearing potential and males must be willing to abstain from heterosexual activity or to use a form of effective method of contraception from the time of informed consent until 30 days after treatment discontinuation.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

* Known hypersensitivity to 5-FU, oxaliplatin or other platinum agents, or any of the components of nal-IRI and other liposomal products.
* Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required prior to enrollment).
* Other active malignancy requiring treatment within the last 2 years. Exceptions include subjects with non-melanoma skin cancer, non-invasive/in situ cancer or low-risk prostate cancer requiring hormonal therapy only.
* Current therapy with other investigational agents or participation in another clinical study (supportive care and nontherapeutic trial participation allowed if not receiving an investigational drug). Participants may participate in prescreening for other therapeutic trials (prescreening of biologic sample for specific mutations, receptors, etc.)
* Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment, except for tumor biopsy or placement of central infusion device (port placement).
* Radiotherapy less than 7 days prior to the start of the study treatment
* Participants who receive nivolumab or pembrolizumab in addition to chemotherapy should not have any contraindications to immune checkpoint inhibitors and should not have received immunotherapy agents for the treatment of EGA prior to study enrollment.

  * Participants must not have active autoimmune disease that has required systemic treatment in the past 2 years. Participants are permitted to receive immunotherapy l if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
  * Participants must not have a condition requiring systemic treatment with either corticosteroids (\>10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study immunotherapy administration. Inhaled or topical steroids and adrenal replacement doses (≤10 mg/day prednisone equivalent) are permitted. Participants with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents.
* Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.
* Active infection requiring systemic therapy.
* Pregnant or breastfeeding.
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
* Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion.
* NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure.
* Known history of Human Immunodeficiency Virus (HIV).

Where this trial is running

Madison, Wisconsin

• University of Wisconsin Carbone Cancer Center — Madison, Wisconsin, United States (Recruiting)

Study contacts

• Principal investigator: Nataliya Uboha, MD, PhD — University of Wisconsin, Madison
• Study coordinator: Cancer Connect

Conditions Esophageal Adenocarcinoma; Gastric Adenocarcinoma