2 Versus 6 Hour Oxaliplatin Infusions in Patients With Gastrointestinal Cancers

Study Overview
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Brief Summary
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This phase II trial studies how well giving oxaliplatin over 6 hours works in treating nerve damage in patients with gastrointestinal cancers. Oxaliplatin can cause side effects such as nerve damage that may delay or reduce the dose of oxaliplatin. Giving oxaliplatin over a longer period of time (6 hours) may prevent or delay the development of nerve damage, which may keep patients on standard doses of chemotherapy longer, without having to delay treatment.

Detailed Description
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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.

Official Title
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Phase II Evaluation of the Effect of 2 Versus 6 Hour Oxaliplatin Infusions on Neuropathy and Pharmacokinetics in Patients With Gastrointestinal Cancers

Conditions
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Malignant Digestive System Neoplasm

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


Participation Criteria
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Eligibility Criteria
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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 with advanced or metastatic disease should have at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients in the adjuvant treatment setting planned to have > 4 cycles of FOLFOX-containing chemotherapy are eligible and will be followed per standard of care 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 any focal or systemic anticancer therapy within 14days 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 14days 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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2-hour infusion group<br>Patients receive oxaliplatin 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. | Drug: Fluorouracil<br>* Given IV<br>* Other names: Ribofluor;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given IV<br>* Other names: Eloxatin;|
| Experimental: 6-hour infusion group<br>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. | Drug: Fluorouracil<br>* Given IV<br>* Other names: Ribofluor;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given IV<br>* Other names: Eloxatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of 2 versus 6-hour oxaliplatin infusion time on 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 | The EORTC-CIPN-20 sub-scales will be computed according to the standard scoring algorithm and then transformed to a 0 to 100 scale, where high scores mean less symptom burden. The primary outcome measure of difference in sensory scores of the two groups between baseline and the initiation of cycle 4 will be the driver of the analysis. | Baseline up to 60 days (course 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentrations achieved (Cmax) | The study will focus on maximum concentrations achieved (Cmax) with each infusion time. Data will be analyzed using non-compartmental methods via Phoenix WinNonlin analytical software, version 8.0 or higher. | At baseline and at 1, 2, 4, 6, 48, and 192 hours after initiation of oxaliplatin | 
| Changes in tumor size | The study will assess changes in tumor size per standard of care assessments at screening and every 2 months. | Up to 18 months after completion or discontinuation of chemotherapy | 
| Duration of therapy | Duration of therapy will be recorded. | Up to 18 months after completion or discontinuation of chemotherapy | 
| Dose density | Dose density will be recorded. | Up to 18 months after completion or discontinuation of chemotherapy | 
| Frequency of dose holds or reductions | Frequency of dose holds or reductions will be recorded. | Up to 18 months after completion or discontinuation of chemotherapy |