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

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.

• Nab-paclitaxel 150 mg/m^2 (Drug), also known as Abraxane®: Stage I (N=12), on day 1 and day 15 Stage II (N= 25), on day 1 and day 15
• Oxaliplatin 85 mg/m^2 (Drug), also known as Eloxatin: Stage I (N= 12), on day 1 and day 15 Stage II (N= 25), on day 1 and day 15
• 5-FU 1200 mg/m^2 x 2 D (Drug), also known as Adrucil, Fluorouracil: Stage I (N= 12), on day 1 and day 15-16 Stage II (N= 25),on day 1 and day 15-16
• Leucovorin 400 mg/m^2 (Drug): Stage I (N= 12),on day 1 and day 15 Stage II (N= 25), on day 1 and day 15

Primary outcomes

• Objective Response Rate [From C1D1 until death or up to a maximum of 36 months]: Objective response rate will be calculated by combining the number of subjects who achieve complete response and partial response per RECIST 1.1 criteria.Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm.

Secondary outcomes

• Overall Survival (OS) [From C1D1 until death or up to a maximum of 52 months]: Overall survival is defined by the date of the start of treatment to date of death from any cause.
• Progression-Free Survival (PFS) [From C1D1 until death or up to a maximum of 36 months]: Progression free survival is defined as the time of treatment initiation until the criteria for disease progression per RECIST1.1 are met or until the date of a death event (any cause). Progressive disease 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 5mm. (Note: the appearance of one or more new lesions is also considered progressions).
• Time to Progression (TTP) [From C1D1 until PD or up to a maximum of 36 months]: Time to progression is defined as the time from registration date until the criteria for disease progression per RECIST1.1 are met. Progressive disease 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 5mm. (Note: the appearance of one or more new lesions is also considered progressions).
• Number of Subjects Achieve Best Overall Response of CR, PR, SD and PD [From C1D1 until PD or up to a maximum of 36 months]: Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. Stable disease is defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive disease 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 5mm. (Note: the appearance of one or more new lesions is also considered progressions).
• Disease Control Rate (DCR) [From C1D1 until PD or up to a maximum of 36 months]: The disease control rate is the proportion of all subjects with stable disease (SD) , or partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment). Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. Stable disease is defined neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• Safety and Toxicity Profile of the Combination of Nab-paclitaxel and FOLFOX [From C1D1 until death or up to a maximum of 52 months]: Safety and tolerability of abemaciclib in the combination of nab-paclitaxel and FOLFOX in patients with metastatic or advanced unresectable gastric, gastro-esophageal junction adenocarcinoma., assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Objective Response Rate (Primary), Count of participants, Participants: Nab-paclitaxel and FOLFOX-A 15
• Overall Survival (OS) (Secondary), Median, months: Nab-paclitaxel and FOLFOX-A 10.6 (8.8 to 20.7)
• Progression-Free Survival (PFS) (Secondary), Median, months: Nab-paclitaxel and FOLFOX-A 6.6 (5.7 to 12.9)
• Time to Progression (TTP) (Secondary), Median, months: Nab-paclitaxel and FOLFOX-A 11.26 (5.68 to 26.65)
• Number of Subjects Achieve Best Overall Response of CR, PR, SD and PD (Secondary), Count of participants, Participants: Nab-paclitaxel and FOLFOX-A 1
• Disease Control Rate (DCR) (Secondary), Number, percentage of participants: Nab-paclitaxel and FOLFOX-A 80
• Safety and Toxicity Profile of the Combination of Nab-paclitaxel and FOLFOX (Secondary), Count of participants, Participants: Nab-paclitaxel and FOLFOX-A 38

Adverse events

Time frame: Adverse events were assessed from week 1 of treatment and every chemotherapy cycles thereafter, for up to 52 months or until unacceptable toxicity. All-Cause Mortality was assessed from week 1 of treatment and every chemotherapy cycles thereafter, for up to 52 months or until unacceptable toxicity

Serious adverse events by term

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2021-02-15)

• Al B. Benson, MD, Principal investigator, Big Ten Cancer Research Consortium