FOLFOX-A in the Treatment of Metastatic or Advanced Unresectable Gastric, Gastro-Esophageal Junction Adenocarcinoma

Study Overview
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Brief Summary
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This is an open label, single-arm phase II, multi-institutional trial to evaluate the efficacy and safety of the combination of nab-paclitaxel and FOLFOX (FOLFOX-A) as first line therapy for patients diagnosed with histologically-confirmed advanced gastric/GEJ adenocarcinoma.

Detailed Description
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All patients will receive FOLFOX-A on days 1 and 15 of each cycle (1 cycle = 28 days). Nab-paclitaxel will be given at a dose of 150 mg/m2 IV over 30 minutes, followed by oxaliplatin IV 85 mg/m2 and leucovorin IV 400 mg/m2 over 2 hours, and 5-FU as a continuous IV infusion over Day 1 and Day 2 (for a total dose of 2400mg/m2 over 46-48 hours.). Radiographic assessment will be performed at baseline and every other cycle (starting with Cycle 3) to evaluate response to treatment by RECIST Version 1.1 guidelines. Patients may continue to receive treatment until disease progression or unacceptable toxicity.

Official Title
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A Phase II Study of FOLFOX Combined With Nab-Paclitaxel (FOLFOX-A) in the Treatment of Metastatic or Advanced Unresectable Gastric, Gastro-Esophageal Junction Adenocarcinoma. Big Ten Cancer Research Consortium: BTCRC-GI15-015

Conditions
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Gastro-Esophageal Junction Adenocarcinoma, Gastric Cancer

Intervention / Treatment
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* Drug: Nab-paclitaxel 150 mg/m^2
* Drug: Oxaliplatin 85 mg/m^2
* Drug: 5-FU 1200 mg/m^2 x 2 D
* Drug: Leucovorin 400 mg/m^2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must meet all of the following applicable inclusion criteria to participate in this study: 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. Age ≥ 18 years at the time of consent. ECOG Performance Status of 0-1 within 28 days prior to registration. Histologically-confirmed advanced or metastatic unresectable gastric carcinoma, or adenocarcinoma of the gastroesophageal junction. Prior neoadjuvant or adjuvant chemotherapy, hormonal therapy, immunotherapy, radiation or chemoradiotherapy must have been completed at least 6 months prior to documented recurrence or metastatic disease. NOTE: patients must not have received previous systemic treatment for metastatic disease. Evaluable disease according to RECIST v1.1 for solid tumors, within 28 days prior to registration. Demonstrate adequate organ function as described below; all screening labs to be obtained within 28 days prior to registration. Bilirubin < 1.5 mg/dL Patients must have adequate liver function: AST and ALT < 2.5 x upper limit of normal, alkaline phosphatase < 2.5 x upper limit of normal, unless bone or liver metastasis is present (≤5 x upper limit of normal). Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3 (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to laboratory sample), Hemoglobin > 9.0g/dL and ANC > 1,500 cells/mm3. Patients must have adequate renal function: creatinine <1.5 mg/dL or creatinine clearance ≥60mL/min is recommended; however, institutional norms are acceptable. Females of child-bearing potential (defined as a sexually mature woman who (1) has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must: Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis), or agree to use and be able to comply with effective contraception without interruption 28 days prior to starting investigational product (IP), and while on study medication (including dose interruptions) and for 30 days following the last dose of IP; and Have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing pregnancy testing prior to each treatment and after the end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact. Male subjects must practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months following IP discontinuation, even if he has undergone a successful vasectomy. NOTE: True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. Exclusion Criteria Subjects meeting any of the criteria below may not participate in the study: Her-2 positive gastric tumor. Treatment with any investigational products within 28 days prior to study registration. Preexisting peripheral neuropathy is not allowed from any cause. Known history of Human Immunodeficiency Virus (HIV) or Hepatitis C (baseline testing is not required). Patients with active sepsis or pneumonitis Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to trial registration 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 registration. Known hypersensitivity to fluorouracil (5-FU), oxaliplatin, or other platinum agents. Known hypersensitivity to nab-paclitaxel or any of its excipients. History of slowly progressive dyspnea and unproductive cough, or pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis or multiple allergies. See section 6.5.1. Has known dihydropyrimidine dehydrogenase deficiency (DPD) deficiency (testing not required) Ongoing or active infection requiring systemic treatment (must be afebrile for ≥ 48 hours prior to study registration) Uncontrolled intercurrent illness including, but not limited to any of the following: Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). Known additional malignancy within the past 3 years. Exceptions include treated localized basal cell or squamous cell carcinoma of the skin, in situ cervical or vulvar carcinoma that has undergone potentially curative therapy, superficial bladder tumors (Ta, Tis & T1), ductal carcinoma in situ (DCIS) of the breast and low grade prostate cancer (Gleason sore 6). Any cancer curatively treated > 3 years prior to registration with no clinical evidence of recurrence is permitted. Psychiatric illness/social situations that would limit compliance with study requirements. Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

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 Arm<br>All patients in Stage I (N=12) and Stage II (N=25) will receive FOLFOX-A on days 1 and 15 of each cycle (1 cycle = 28 days). Nab-paclitaxel will be given at a dose of 150 mg/m^2 IV over 30 minutes, followed by oxaliplatin IV 85 mg/m^2 and leucovorin IV 400 mg/m^2 over 2 hours, and 5-FU as a continuous IV infusion over Day 1 and Day 2 (for a total dose of 2400mg/m^2 over 46-48 hours.). Radiographic assessment will be performed at baseline and every other cycle (starting with Cycle 3) to evaluate response to treatment by RECIST Version 1.1 guidelines. Patients may continue to receive treatment until disease progression or unacceptable toxicity. | Drug: Nab-paclitaxel 150 mg/m^2<br>* Stage I (N=12), on day 1 and day 15 Stage II (N= 25), on day 1 and day 15<br>* Other names: Abraxane®;Drug: Oxaliplatin 85 mg/m^2<br>* Stage I (N= 12), on day 1 and day 15 Stage II (N= 25), on day 1 and day 15<br>* Other names: Eloxatin;Drug: 5-FU 1200 mg/m^2 x 2 D<br>* Stage I (N= 12), on day 1 and day 15-16 Stage II (N= 25),on day 1 and day 15-16<br>* Other names: Fluorouracil;Drug: Leucovorin 400 mg/m^2<br>* Stage I (N= 12),on day 1 and day 15 Stage II (N= 25), on day 1 and day 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Response Rate | partial or complete response of FOLFOX combined with nab-paclitaxel (FOLFOX-A) in patients with advanced gastric, gastroesophageal junction adenocarcinoma | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | will be estimated using the method of Kaplan-Meier and univariate testing will be done via the log rank test (median time to event) | 2 years | 
| Progression-Free Survival (PFS) | will be estimated using the method of Kaplan-Meier and univariate testing will be done via the log rank test (median time to event) | 2 years | 
| Time to Progression (TTP) | will be estimated using the method of Kaplan-Meier and univariate testing will be done via the log rank test (median time to event) | 2 years | 
| Best Overall Response Rate (ORR) | will be summarized by count and percent of subjects with each ordinal response analyzed by Cochran-Mantel-Hanzel test | 2 years | 
| Best Disease Control Rate (DCR) | will be summarized by count and percent of subjects with each ordinal response analyzed by Cochran-Mantel-Hanzel test | 2 years | 
| Adverse Events | grade 3 and 4 adverse events defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4 | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FOLFOX, Nab-Paclitaxel