Aldesleukin With Nivolumab and Standard Chemotherapy for Treatment of Gastric Cancer With Peritoneal Metastasis

Study Overview
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Brief Summary
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This phase Ib trial test effects of aldesleukin in combination with nivolumab and standard chemotherapy in treating patients with gastric cancer that has spread to the tissue lining of the abdomen (peritoneal metastasis). Aldesleukin is similar to a protein that naturally exists in the body that stimulates the immune system to fight infections. 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. Chemotherapy drugs, such as leucovorin calcium, fluorouracil, and oxaliplatin, 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. Giving aldesleukin in combination with nivolumab and standard chemotherapy may work better in treating patients with gastric cancer with peritoneal metastasis.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the reduction in the peritoneal carcinomatosis index (PCI) after completion of the study treatment. SECONDARY OBJECTIVES: I. Evaluate histological response of the peritoneal metastasis to study treatment using the peritoneal regression grading score (PRGS). II. Assess overall survival (OS). III. Assess progression-free survival (PFS). IV. Assess safety and tolerability of the study regimen. TERTIARY AND CORRELATIVE RESEARCH OBJECTIVES: I. Assess the number and percentage of patients that successfully undergo complete cytoreductive surgery after treatment. II. Evaluate for helper T cell, cytotoxic T cell, natural killer (NK) cells as well as T-reg cells in blood and peritoneal fluid. III. Evaluate the neutrophilic, lymphocytic, and eosinophilic infiltration of tumor using a standardized classification. OUTLINE: Patients receive aldesleukin intraperitoneally (IP) on study. Patients also receive standard of care nivolumab intravenously (IV), leucovorin calcium IV, fluorouracil IV, and oxaliplatin IV on study. Patients also undergo diagnostic laparoscopy with biopsy, positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI), and collection of blood and tissue samples throughout the trial.

Official Title
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COordinated Nivolumab and IntraperiToneal IL-2 for Gastric CanceR With PeritOneaL Metastasis (CONTROL) Phase 1b Pilot Study

Conditions
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Clinical Stage IV Gastric Cancer AJCC v8, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Metastatic Gastric Carcinoma, Metastatic Malignant Neoplasm in the Peritoneum

Intervention / Treatment
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* Biological: Aldesleukin
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Diagnostic Laparoscopy
* Drug: Fluorouracil
* Drug: Leucovorin Calcium
* Procedure: Magnetic Resonance Imaging
* Biological: Nivolumab
* Drug: Oxaliplatin
* Procedure: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION: Age >= 18 years PRE-REGISTRATION: Disease characteristics Histological confirmation of adenocarcinoma of the stomach or gastroesophageal junction (GEJ) Currently receiving first-line therapy with leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) and nivolumab without evidence of disease progression OR planning to start first-line therapy with FOLFOX and nivolumab PRE-REGISTRATION: No radiographic or histological evidence of non-peritoneal metastasis PRE-REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 PRE-REGISTRATION: Willingness to provide mandatory blood specimens for correlative research PRE-REGISTRATION: Willingness to provide mandatory tissue specimens for correlative research PRE-REGISTRATION: Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) REGISTRATION: Peritoneal Carcinomatosis Index (PCI) >= 1 and =< 24 obtained =< 30 days prior to registration REGISTRATION: Clinical, pathological, or radiographic evidence of peritoneal metastasis per PCI and Peritoneal Regression Grading Score (PRGS) REGISTRATION: Hemoglobin >= 8.0 g/dL (obtained =< 15 days prior to registration) REGISTRATION: Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 15 days prior to registration) REGISTRATION: Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration) REGISTRATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 15 days prior to registration) REGISTRATION: Alanine aminotransferase (ALT) AND aspartate transaminase (AST) =< 1.5 x ULN (obtained =< 15 days prior to registration) REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy, then INR or aPTT is within target range of therapy (obtained =< 15 days prior to registration) REGISTRATION: Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 15 days prior to registration) REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only REGISTRATION: Provide written informed consent REGISTRATION: Willingness to provide mandatory blood specimens for correlative research REGISTRATION: Willingness to provide mandatory tissue specimens for correlative research REGISTRATION: Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Exclusion Criteria: PRE-REGISTRATION: Any of the following because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects: Pregnant persons Nursing persons Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception PRE-REGISTRATION: Any of the following prior therapies: IL-2 or chronic corticosteroids, or immunosuppressive agents NOTE: Inhaled corticosteroids are allowed PRE-REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens PRE-REGISTRATION: Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Or psychiatric illness/social situations that would limit compliance with study requirements Autoimmune disease PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm PRE-REGISTRATION: Active second malignancy currently receiving systemic treatment =< 6 months prior to pre-registration PRE-REGISTRATION: History of myocardial infarction =< 6 months prior to pre-registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias REGISTRATION: Identification of non-peritoneal metastasis during laparoscopy REGISTRATION: Any of the following because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects: Pregnant persons Nursing persons Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception REGISTRATION: Any of the following therapies: prior immune checkpoint inhibitors, prior IL-2, or chronic corticosteroids or immunosuppressive agents NOTE: Inhaled corticosteroids are allowed. One-time antiemetic dose is allowed REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens REGISTRATION: Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy REGISTRATION: Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Or psychiatric illness/social situations (e.g., substance abuse) that would limit compliance with study requirements Autoimmune disease requiring systemic treatment Small bowel obstruction REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm REGISTRATION: Active malignancy currently receiving systemic treatment =< 6 months prior to registration REGISTRATION: History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias REGISTRATION: Small bowel obstruction < 15 days prior to registration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (aldesleukin, nivolumab, chemotherapy)<br>Patients receive aldesleukin IP on study. Patients also receive standard of care nivolumab IV, leucovorin calcium IV, fluorouracil IV, and oxaliplatin IV on study. Patients also undergo diagnostic laparoscopy with biopsy, PET/CT or PET/MRI, and collection of blood and tissue samples throughout the trial. | Biological: Aldesleukin<br>* Given IP<br>* Other names: Recombinant Human Interleukin-2;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood and tissue samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Procedure: Diagnostic Laparoscopy<br>* Undergo diagnostic laparoscopy<br>Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Procedure: Magnetic Resonance Imaging<br>* Undergo PET/MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Procedure: Positron Emission Tomography<br>* Undergo PET/CT or PET/MRI<br>* Other names: PT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of reduction in the peritoneal carcinomatosis index |  | About 90 days after last dose of aldesleukin (IL-2) | 
| Incidence of adverse events |  | About 90 days after last dose of aldesleukin (IL-2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological response of the peritoneal metastasis | Will be assessed using the peritoneal regression grading score. Will be reported descriptively, including reporting of frequencies, percentages and 95% confidence intervals. | About 90 days after last dose of aldesleukin (IL-2) | 
| Progression free survival | Summary statistics, including the median and other various timepoints will be reported as well as 95% confidence intervals. | From study entry to the first of either disease progression or death, assessed up to 3 years | 
| Overall survival | Summary statistics, including the median and other various timepoints will be reported as well as 95% confidence intervals. | From date of study entry to date of death or last follow up, assessed up to 3 years |