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mFOLFIRINOX Versus mFOLFOX With or Without Nivolumab for the Treatment of Advanced, Unresectable, or Metastatic HER2 Negative Esophageal, Gastroesophageal Junction, and Gastric Adenocarcinoma

ConditionsAdvanced Esophageal AdenocarcinomaAdvanced Gastric AdenocarcinomaAdvanced Gastroesophageal Junction AdenocarcinomaClinical Stage III Esophageal Adenocarcinoma AJCC v8Clinical Stage III Gastric Cancer AJCC v8Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8Clinical Stage IV Esophageal Adenocarcinoma AJCC v8Clinical Stage IV Gastric Cancer AJCC v8Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8Metastatic Esophageal AdenocarcinomaMetastatic Gastric AdenocarcinomaMetastatic Gastroesophageal Junction AdenocarcinomaUnresectable Esophageal AdenocarcinomaUnresectable Gastric AdenocarcinomaUnresectable Gastroesophageal Junction Adenocarcinoma
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorAlliance for Clinical Trials in Oncology

About this trial

This phase III trial compares the effect of modified fluorouracil, leucovorin calcium, oxaliplatin, and irinotecan (mFOLFIRINOX) with or without nivolumab to the effect of modified fluorouracil, leucovorin calcium, and oxaliplatin (mFOLFOX) with or without nivolumab for the treatment of patients with advanced, unresectable, or metastatic HER2 negative esophageal, gastroesophageal junction, or gastric adenocarcinoma. The usual approach for patients who are not in a study is treatment with FOLFOX with some receiving an immunotherapy drug, either nivolumab or pembrolizumab, in addition to FOLFOX chemotherapy. The usual approach is defined as care most people get for cancer in the stomach, esophagus, or gastroesophageal junction. Fluorouracil is in a class of medications called antimetabolites. It stops cells from making DNA and may kill tumor cells. Leucovorin in a class of medications called folic acid analogs. When used with fluorouracil it enhances the effects of this chemotherapy drug. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and DNA repair, and may kill cancer cells. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill cancer cells. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Some patients on this trial will receive nivolumab, in addition to mFOLFOX or mFOLFIRINOX chemotherapy. mFOLFIRINOX with or without nivolumab may be more effective than mFOLFOX with or without nivolumab by shrinking the tumor in patients with advanced, unresectable, or metastatic HER2-negative esophageal, gastroesophageal junction, or gastric adenocarcinoma.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Histologic documentation: HER2 negative adenocarcinoma as defined by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines (Bartley et al., Journal of Clinical Oncology [JCO] 2017) with known PD-L1 combined positive score (CPS) (any CPS is allowed, but should be known prior to registration)

Stage: unresectable or metastatic

Tumor site: esophagus, gastroesophageal junction, or stomach

Measurable disease or non-measurable but evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Disqualifiers

None

Trial design

Design model

Parallel

Treatments tested in this trial

  • Fluorouracil

    Drug

    Given IV

  • Leucovorin Calcium

    Drug

    Given IV

  • Oxaliplatin

    Drug

    Given IV

  • Irinotecan

    Drug

    Given IV

  • Nivolumab

    Biological/Vaccine

    Given IV

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Computed Tomography

    Procedure/Surgery

    Undergo a CT Scan

  • Biospecimen Collection

    Procedure/Surgery

    Undergo blood sample collection

  • Questionnaire Administration

    Other intervention

    Ancillary studies

Treatment groups

382 Participants
are divided into 2 treatment groups
Group A: Arm I (mFOLFIRINOX, nivolumab)Experimental treatment 9 interventions
Group B: Arm II (mFOLFOX, nivolumab)Active comparator 8 interventions

Trial outcomes

Primary outcomes

1

Overall survival (OS)

Will compare the distributions of OS between the two treatment arms to determine if patients treated with modified fluorouracil, leucovorin calcium, oxaliplatin, and irinotecan (mFOLFIRINOX) (with or without nivolumab) have an OS benefit compared to those treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (with or without nivolumab). Kaplan-Meier methodology will be used to estimate the distributions for the treatment arms. To compare the OS distributions between the two treatment arms, we will use a one-sided logrank test to evaluate if mFOLFIRINOX (with or without nivolumab) is superior to mFOLFOX (with or without nivolumab) based on an intention to treat analysis. The hazard ratio, median OS, and estimated OS rates at 1 and 2 years will be estimated along with corresponding 95% confidence intervals. Multivariable Cox proportional hazards models will also be used to assess the impact of treatment arm on OS when stratifying on the stratification factors.

Time frame
Up to 2 years from the time of randomization.

Secondary outcomes

1

Progression-free survival (PFS)

PFS will be evaluated as a time to event outcome and compared in a secondary manner between the two treatment arms. Patients who are alive and progression-free at their last evaluation will be censored at that time point.

Time frame
The time from registration to the time of documented progression and/or death, assessed up to 3 years
2

Overall response rate

The best response achieved after initiation of therapy on protocol will also be assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and will be summarized by treatment arm. The overall response rate will be calculated as the number of patients who achieve a response (partial response, complete response) divided by the total number of patients randomized to the corresponding treatment arm.

Time frame
Up to 3 years
3

Duration of Response

Time frame
The time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 3 years
4

Incidence of adverse events

The toxicity and tolerability of each of these regimens will be evaluated and captured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5, where the type and severity grade of each adverse event will be collected and tabulated within each of the treatment arms. Perceived attribution to study treatment will also be captured. Tolerability will further be assessed by summarizing the numbers of patients who require dose modifications or delays, and reasons for patients to go off treatment.

Time frame
Up to 3 years

Other outcomes

1

Exploratory correlative markers

Exploratory correlative markers will also be measured and evaluated within and between arms to better assess mechanisms and prognostic impact of markers on impact. These will include baseline PD-L1 combined positive score and cell free deoxyribonucleic acid during the treatment.

Time frame
Up to 3 years
2

Incidence of adverse events

Will evaluate the delinquency rate for the standard adverse event (AE) case report forms (CRFs) for this trial over the course of the trial and compare this to the proportion of patients with delinquent AE CRFs on other phase III trials conducted during the same time frame as this trial.

Time frame
up to 3 years
3

Feasibility and compliance of intervention

Finally, we will also collect data related feasibility and compliance in term of the number of queries received by participating sites regarding questions on attribution collection as well as if any attribution is forcibly submitted using the comments fields.

Time frame
Up to 3 years

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Alliance for Clinical Trials in Oncology

Lead sponsor

National Cancer Institute (NCI)

Collaborator

Source ClinicalTrials.gov
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