Gastrointestinal Cancer A022102

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.

PRIMARY OBJECTIVE:

  1. To determine if overall survival (OS) is improved in patients who received mFOLFIRINOX +/- nivolumab in comparison to FOLFOX +/- nivolumab as first-line chemotherapy for metastatic gastroesophageal adenocarcinoma.

SECONDARY OBJECTIVES:

  1. To compare other indices of efficacy, including progression-free survival, objective response rates and duration of response between both treatment arms.
  2. To evaluate safety and tolerability associated with treatment in each of the treatment arms.
  3. To evaluate the proportion of patients receiving second line of therapy in both arms.
  4. To evaluate tolerability of the treatment in both arms using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Inclusion Criteria:

  • Histologic documentation: HER2 negative adenocarcinoma
  • Stage: unresectable or metastatic
  • Tumor site: esophagus, gastroesophageal junction, or stomach
  • No prior treatment for unresectable or metastatic disease
  • Prior neoadjuvant or adjuvant cytotoxic chemotherapy or adjuvant immunotherapy is allowed as long as it was completed at least 1 year prior to registration
  • Age >= 18 years
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:
    On effective anti-retroviral therapy
  • Undetectable HIV viral load by standard clinical assay =< 6 months of registration
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • Patients who will receive nivolumab in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors
  • Patients must not have a condition requiring systemic treatment with either corticosteroids (>10mg/day prednisone equivalents) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids and adrenal replacement doses (=< 10mg/day prednisone equivalent) are permitted
  • Patients must not have a history of noninfectious pneumonitis requiring steroids
  • Patients with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents are ineligible
  • This study includes the use of the mandatory patient completed measure, PRO-CTCAE. For this study the PRO-CTCAE is available in English, Spanish, Korean, Chinese (Simplified), and Russian, hence patients must be able to speak, understand and read in these languages. Ad-hoc translation of patient-reported measures is not permitted

Exclusion Criteria:

  • Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
  • No known Gilbert's syndrome or known homozygosity for UGAT1A1*28 polymorphism
  • No baseline grade >= 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per CTCAE version (v) 5.0 regardless of causality
  • No medical condition such as uncontrolled infection or uncontrolled diabetes mellitus which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
  • No untreated, symptomatic brain metastasis. Patients with treated brain metastases are eligible if the following criteria are met: 1) follow-up brain imaging done at least in 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and 2) the patient no longer requires steroids, or is on a stable steroid dose for more than four weeks
  • No allogeneic tissue/organ transplant

Locations: HH, Manchester, Avon, HOCC, MMC

Contacts: Siobhan Reilly 860.696.4958 Siobhan.Reilly@hhchealth.org; Hayley Dunnack Yackel 860.972.5518 Hayley.Dunnack@hhchealth.org

Sponsor(s): Alliance for Clinical Trials in Oncology

Cancer Clinical Research Office