Oxaliplatin Microdosing Assay in Predicting Exposure and Sensitivity to Oxaliplatin-Based Chemotherapy

Study Overview
=================
Brief Summary
-----------------
This pilot clinical trial studies how well carbon C 14 oxaliplatin microdosing assay works in predicting exposure and sensitivity to oxaliplatin-based chemotherapy in patients with colorectal cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Carbon C 14 is a radioactive form of carbon, exists in nature and in the body at a low level. Microdose carbon C 14 oxaliplatin diagnostic assay may help doctors understand how well patients respond to treatment and develop individualize oxaliplatin dosing in patients with colorectal cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the feasibility of [14C] (carbon C 14) oxaliplatin microdose as a clinical assay to predict oxaliplatin exposure. SECONDARY OBJECTIVES: I. To estimate the degree to which a [14C]oxaliplatin microdose predicts the observed pharmacokinetics of standard dose oxaliplatin. II. To validate that intrapatient variation of exposure to a [14C]oxaliplatin microdose is less than 5%. III. To detect the levels of oxaliplatin-deoxyribonucleic acid (DNA) adducts induced by oxaliplatin microdosing in peripheral blood mononuclear cells (PBMCs), and correlate the results with patient response and progression free survival on oxaliplatin-based chemotherapy. IV. To develop preliminary safety data of [14C]oxaliplatin microdosing for future studies. OUTLINE: Patients receive carbon C 14 oxaliplatin microdose intravenously (IV) over 120 minutes. Beginning not more than 4 weeks after the initial carbon C 14 oxaliplatin microdose administration, patients receive FOLFOX comprised of leucovorin calcium IV, fluorouracil IV over 2 hours (over 46-48 hours via ambulatory infusion pump on days 1 and 2), and oxaliplatin (contain carbon C 14 microdose course I only) IV over 2 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
-----------------
Pilot Study of a Carbon 14 Oxaliplatin Microdosing Assay to Predict Exposure and Sensitivity to Oxaliplatin-Based Chemotherapy in Advanced Colorectal Cancer

Conditions
-----------------
Colon Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Carbon C 14 Oxaliplatin
* Drug: Oxaliplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed locally advanced or metastatic colon or rectal adenocarcinoma Intent to treat the patient with a leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy regimen containing fluorouracil (5-FU), leucovorin, and oxaliplatin according to clinical standard practice; the intent should be to dose oxaliplatin at 85 mg/m^2 on an every 2 week basis Treatment with any additional Food and Drug Administration (FDA)-approved biologic agent (i.e. bevacizumab, cetuximab, or panitumumab) is allowed according to standard practice Prior radiation or surgery is allowed, but should be finished at least 2 weeks prior to study enrollment; if a participant has prior radiation therapy, at least one measurable lesion outside of the radiation field should be available for the evaluation of response to chemotherapy Any number of prior therapies other than oxaliplatin is allowed Zubrod performance status equal to or less than 2 (Karnofsky equal to or greater than 50%) Life expectancy of at least 3 months Absolute neutrophil count greater than or equal to 1,500/microL Platelets greater than or equal to 100,000/microL Total bilirubin less than 3 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase) less than or equal to 5 x ULN Creatinine less than 1.5 x ULN Women of child bearing potential must not be pregnant; a pre-study pregnancy test must be negative Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation Men must agree to use adequate contraception (barrier method or abstinence) prior to study entry and for 30 days after study participation Ability to understand and willing to sign a written informed consent document Exclusion Criteria: Prior treatment with oxaliplatin Patients must not receive concomitant radiation 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 Participants who are pregnant or nursing Participants who are allergic to any platinum agent Participants who have more than grade 1 peripheral neuropathy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: carbon C 14 oxaliplatin and oxaliplatin<br>Patients receive carbon C 14 oxaliplatin microdose IV over 120 minutes. Beginning not more than 4 weeks after the initial carbon C 14 oxaliplatin microdose administration, patients receive FOLFOX6 comprised of leucovorin calcium IV, fluorouracil IV over 2 hours (over 46-48 hours via ambulatory infusion pump on days 1 and 2), and oxaliplatin (contain carbon C 14 microdose course I only) IV over 2 hours on day 1. | Drug: Carbon C 14 Oxaliplatin<br>* Intravenous infusion<br>* Other names: [14C] Oxaliplatin;Drug: Oxaliplatin<br>* Intravenous infusion<br>* Other names: Eloxatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of 14C Oxaliplatin Microdose as a Clinical Assay to Predict Oxaliplatin Exposure | Correlate area under curve from phase 0 microdosing with area under curve for therapeutic dose of oxaliplatin | 0-5 minutes predose, 5, 15, and 30 minutes, and at 1, 2, 4, 8, and 24 hours after carbon C 14 oxaliplatin microdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Disease Control (DDC) According to RECIST 1.1 | Will characterize the repair of DNA adducts in PBMC, using descriptive statistics. | Up to 2 years | 
| Number of Participants With Adverse Events According to CTCAE Version 4 | Assess toxicity to both microdoses of carbon C 14 oxaliplatin. Toxicities potentially related to carbon C 14 oxaliplatin will be assessed from initiation of the study to at least 14 days after the administration of the FOLFOX-integrated microdose or until full recover of toxicity (whichever is longer). Safety will be assessed through summaries of adverse events and laboratory evaluations. | Approximately 2 months | 
| Response Rate Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Response was determined according to RECIST criteria as either partial response (PR) or one almost complete response (CR) or progressive disease (PD). | Up to 2 years |