Combination Chemotherapy in Treating Patients With Advanced Stomach, Gastroesophageal, or Esophageal Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well combination chemotherapy works in treating patients with advanced stomach, gastroesophageal, or esophageal cancer. Drugs used in chemotherapy, such as irinotecan hydrochloride, oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Official Title
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Phase II Study of FOLFIRINOX Chemotherapy for Treatment of Advanced Gastric, Gastro-esophageal Junction, and Esophageal Tumors

Conditions
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Stomach Neoplasms, Esophageal Neoplasms

Intervention / Treatment
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* Drug: Irinotecan
* Drug: Trastuzumab
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven and inoperable locally advanced, recurrent, or metastatic cancer of the esophagus, stomach, or gastro-esophageal junction. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. Prior single modality radiation therapy is allowed. At least 18 years of age. ECOG performance status ≤ 2 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal LVEF ≥ 50% Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (legally authorized representative is allowed). Patients already receiving treatment with FOLFIRINOX +/- trastuzumab may participate in the study and have their data collected retrospectively if they met inclusion criteria at the start of therapy and sign consent for study participation moving forward. Exclusion Criteria: Chemotherapy in the 6 months prior to registration. Any active malignancy within 3 years that may alter the course of esophageal cancer (Apparently cured localized malignancy or advanced, but indolent malignancy with significantly more favorable prognosis are allowed) Receiving any other investigational agents at the time of registration. Known untreated brain metastases. These patients must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in the study. Previous therapy for metastatic gastroesophageal cancer. Previous perioperative chemotherapy is allowed as long as the duration without treatment has been greater than 6 months.. A history of congestive heart failure, transmural myocardial infarction, symptomatic valvular disease, or high-risk arrhythmia. 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. Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 14 days of study entry. Known HIV-positivity and on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with trastuzumab. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. Inclusion of Women and Minorities Both men and women and members of all races and ethnic groups are eligible for this trial.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: FOLFIRINOX (HER2-negative)<br>Irinotecan 180 mg/m2 IV on Days 1 & 15. Oxaliplatin 85 mg/m2 IV on Days 1 & 15. Leucovorin 400 mg/m2 IV on Days 1 & 15. Fluorouracil 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 and Day 15. | Drug: Irinotecan<br> <br> * Other names: CPT-11;Drug: Oxaliplatin<br> <br> * Other names: Eloxatin®;Drug: Leucovorin<br> <br> * Other names: citrovorum factor;Drug: Fluorouracil<br> <br> * Other names: 5-FU;|
| Experimental: Arm B: FOLFIRINOX & Trastuzumab (HER2-positive)<br>Trastuzumab 8 mg/kg on Cycle 1 Day 1 then 4 mg/kg on Day 15 and Day 1 of all future cycles. Irinotecan 180 mg/m2 IV on Days 1 & 15. Oxaliplatin 85 mg/m2 IV on Days 1 & 15. Leucovorin 400 mg/m2 IV on Days 1 & 15. Fluorouracil 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 and Day 15. | Drug: Irinotecan<br> <br> * Other names: CPT-11;Drug: Trastuzumab<br> <br> * Other names: Herceptin®;Drug: Oxaliplatin<br> <br> * Other names: Eloxatin®;Drug: Leucovorin<br> <br> * Other names: citrovorum factor;Drug: Fluorouracil<br> <br> * Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Objective Response | Objective response (defined as complete response (CR) + partial response (PR) by RECIST 1.1 criteria) CR: Disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Through completion of treatment (estimated to be 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Duration of time from start of treatment to time of progression or death, whichever occurs first. | Through 1 year after completion of treatment (median follow-up 16.2 months - 95% CI 4.7-42.5 months) | 
| Time to Progression (TTP) | Duration of time from start of treatment to time of progression. Progression is defined as At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Through 1 year after completion of treatment (median follow-up 16.2 months - 95% CI 4.7-42.5 months) | 
| Overall Survival (OS) | Overall survival is defined as the time interval from date of diagnosis to date of death from any cause. | Through 1 year after completion of treatment (median follow-up 16.2 months - 95% CI 4.7-42.5 months) | 
| Clinical Benefit Rate | Clinical benefit rate is the percentage of combined patients who have achieved complete response (CR), partial response (PR), and stable disease (SD) CR: Disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Through completion of treatment (estimated to be 4 months) | 
| Duration of Response | Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented | Through 1 year after completion of treatment (median follow-up 16.2 months - 95% CI 4.7-42.5 months) | 
| Toxicity and Tolerability (Arm A and Arm B) as Measured by the Number of Participants With Grade 3 or Higher Adverse Events |  | 30 days after completion of treatment (estimated to be 5 months) |