2 Versus 6 Hour Oxaliplatin Infusions in Patients With Gastrointestinal Cancers

PRIMARY OBJECTIVE:

I. To determine the effect of 2 versus 6-hour oxaliplatin infusion time on the difference in
severity of sensory neuropathy as measured by patient reported outcome (PRO) scores on the
European Organization for Research and Treatment of Cancer (EORTC) chemotherapy-induced
peripheral neuropathy (CIPN-20) scale at the initiation of cycle 4.

SECONDARY OBJECTIVES:

I. Pharmacokinetic parameters of maximum concentration (Cmax), area under the curve (AUC),
time of maximum concentration (tmax), clearance, and half life (t1/2) of platinum
ultra-filtrate.

II. CIPN-20 sensory score changes over the duration of therapy as measured by a cumulative
area-under-the curve score.

III. Clinical outcomes including duration of therapy, oxaliplatin dose reductions, delays in
therapy, and overall dose intensity and delivery of oxaliplatin.

IV. Relationship between oxaliplatin Cmax, patient-reported acute neurotoxicity, and chronic
neurotoxicity by CIPN-20 scores.

OUTLINE: Patients are randomized to 1 of 2 groups.

2-hour infusion group: Patients receive oxaliplatin intravenously (IV) and leucovorin IV over
2 hours on day 1. Patients also receive a lower dose of fluorouracil IV over 2-4 minutes
followed by a higher dose IV continuous over 4-6 hours on day 1. Courses repeat every 14 days
in the absence of disease progression or unacceptable toxicity.

6-hour infusion group: Patients receive oxaliplatin IV over 6 hours on day 1. Patients also
receive leucovorin and fluorouracil as in the 2-hour infusion group. Courses repeat every 14
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1, 3, 6, 12, and 18 months.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Confirmed diagnosis of a gastrointestinal cancer

- Plan for 4 or more cycles of FOLFOX6 (fluorouracil [with leucovorin] and oxaliplatin)
containing chemotherapy

- Histologically confirmed, measurable or evaluable disease. Patients should have at
least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

- Absolute neutrophil count (ANC) ≥ 1,500/µL (no white blood cell growth factors allowed
to meet requirement)

- Platelets ≥ 75,000/µL (may be transfused up to 72 hours prior to day 1 to meet
requirement)

- Hemoglobin ≥ 8 g/dL (may be transfused up to 72 hours prior to day 1 to meet
requirement)

- Creatinine clearance > 30 mL/min by Cockcroft-Gault, to preserve similar dosing (85
mg/m²) for analysis

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Signed informed consent

- Adequate birth control when appropriate

Exclusion Criteria:

- Any preexisting grade 2 or higher peripheral neuropathy

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of FOLFOX6

- Known intolerance or hypersensitivity to any agent in FOLFOX6 or concurrent agents

- Patients who have any known severe and/or uncontrolled medical conditions such as:

- Unstable angina pectoris, symptomatic heart failure; (New York Heart Association
class III or IV), myocardial infarction ≤ 6 months prior, serious uncontrolled
cardiac arrhythmia, or any other clinically significant cardiac disease

- Active (acute or chronic) or uncontrolled severe infection, liver disease such as
cirrhosis, or decompensated liver disease

- Patients with any history of severe hemorrhage requiring ≥ 4 units of packed red blood
cells (RBCs) in a 48-hour period

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 3 weeks prior to dosing

- Pregnant or nursing (lactating) women

- Women of childbearing potential (WOCBP), defined as all women physiologically capable
of becoming pregnant, must use highly effective methods of contraception during the
study and 8 weeks after. Highly effective contraception methods include combination of
any two of the following:

- Use of oral, injected or implanted hormonal methods of contraception or;

- Placement of an intrauterine device (IUD) or intrauterine system (IUS);

- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;

- Total abstinence or;

- Male/female sterilization Women are considered post-menopausal and not of
childbearing potential if they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks prior to randomization. In the
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of
childbearing potential