Clinical trial NCT02569723
Conditions: Colon Adenocarcinoma
Sponsor: Edward Kim
Start date: 2015-10-16; Completion date: 2020-04-04
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: Carbon C 14 Oxaliplatin intervention 2: Oxaliplatin
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
Pilot Study of a [14C]Oxaliplatin Microdosing Assay to Predict Exposure and 
Sensitivity to Oxaliplatin-Based Chemotherapy  
 
STUDY ID: 
 
 
 
UCDCC#255 
 
VERSION: 
 
 
 
4.0 
 
VERSION DATE: 
 
 
July 14, 2017 
 
PRINCIPAL INVESTIGATOR: 
Edward Kim, MD, PhD 
 
 
 
 
 
UC Davis Comprehensive Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE OF REVISIONS: 
 
VERSION: 
 
DATE: 
Original 
December 17, 2014 
1.1 
July 24, 2015 
1.2 
November 12, 2015 
2.0 
June 02, 2016 
3.0 
4.0 
March 16, 2017 
July 14, 2017 
 
CO-INVESTIGATORS: 
Chong-xian Pan, MD, PhD 
 
 
 
 
University of California Davis Cancer Center 
 
 
 
 
 
 
  
 
 
Paul Henderson, PhD 
 
 
 
 
University of California Davis Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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BIOSTATISTICIAN: 
Susan Stewart, PhD 
 
Division of Biostatistics 
 
University of California,
 
 
  
 
 
 
 
 
IND #:  
 
 
125,533 
  
************************************************************************************************************* 
UC DAVIS COMPREHENSIVE CANCER CENTER ASSUMES NO RESPONSIBILITY FOR 
THE USE OF THIS PROTOCOL OUTSIDE OF PARTICIPATING INSTITUTIONS 
************************************************************************************************************  
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................. 3 
SCHEMA ......................................................................................................................... 5 
1 
OBJECTIVES ........................................................................................................... 6 
1.1 
Primary Objectives ...................................................................................................... 6 
1.2 
Secondary Objectives ................................................................................................. 6 
2 
BACKGROUND ....................................................................................................... 6 
2.1 
Overview of Cancer Treatment with Platinum Agents .............................................. 6 
2.2 
Oxaliplatin .................................................................................................................... 8 
2.3 
Resistance to Platinum-based chemotherapy ........................................................... 9 
2.4 
Accelerator Mass Spectrometry (AMS) .....................................................................11 
2.5 
Prediction of Oxaliplatin Exposure ...........................................................................11 
2.6 
Assessment of Microdose-induced Oxaliplatin-DNA damage .................................12 
2.7 
Rationale for the Current Study .................................................................................13 
3 
DRUG INFORMATION ........................................................................................... 13 
3.1 
Investigational Drug Information ...............................................................................13 
3.2 
Standard of Care Drug Information ...........................................................................17 
4 
ELIGIBILITY CRITERIA ......................................................................................... 23 
4.1 
Inclusion Criteria ........................................................................................................23 
4.2 
Exclusion Criteria .......................................................................................................23 
5 
DESCRIPTIVE/STRATIFICATION FACTORS ....................................................... 24 
6 
STUDY DESIGN AND TREATMENT PLAN .......................................................... 24 
6.1 
Study Design...............................................................................................................24 
6.2 
Selection of Patients ..................................................................................................24 
6.3 
Phase 0 [14C]Oxaliplatin Microdose ...........................................................................24 
6.4 
Cycle 1 [14C]Oxaliplatin Microdose Concurrent with FOLFOX ................................26 
6.5 
FOLFOX Treatment .....................................................................................................27 
6.6 
Follow Up Period ........................................................................................................28 
6.7 
Criteria for Discontinuation .......................................................................................28 
7 
EVENTS TO BE MONITORED and dose modifications ...................................... 28 
7.1 
Safety Assessments ...................................................................................................28 
7.2 
Adverse Events ...........................................................................................................29 
7.3 
Efficacy Assessments ................................................................................................32 
7.4 
Dose Modifications .....................................................................................................33 
8 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .......................... 33 
8.1 
Criteria for Evaluation ................................................................................................33 
8.2 
Endpoint Definitions ...................................................................................................33 
9 
STUDY CALENDAR .............................................................................................. 34 


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10 
SPECIAL INSTRUCTIONS ................................................................................. 35 
10.1 Specimen Collection, Storage, Shipping and Submission Requirements..............35 
10.2 Pharmacokinetics .......................................................................................................36 
10.3 Assessment of Platinum-DNA Adducts in PBMCs ...................................................36 
11 
STATISTICAL CONSIDERATIONS .................................................................... 36 
11.1 Statistical Design ........................................................................................................36 
11.2 Analysis Plan ..............................................................................................................36 
11.3 Sample Size ................................................................................................................37 
12 
REGISTRATION GUIDELINES .......................................................................... 37 
13 
DATA SUBMISSION ........................................................................................... 38 
13.1 Confidentiality of Records .........................................................................................38 
13.2 Patient Consent Form ................................................................................................38 
13.3 Registration Eligibility Worksheet .............................................................................38 
13.4 Data Collection Forms and Submission Schedule ...................................................38 
13.5 Database Management and Quality Control .............................................................38 
14 
MINORITIES AND WOMEN STATEMENT ......................................................... 39 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ......................................... 39 
15.1 Ethical Conduct of the Study .....................................................................................39 
15.2 Informed Consent Procedures ..................................................................................39 
16 
DATA AND SAFETY MONITORING .................................................................. 39 
17 
PATHOLOGY REVIEW ....................................................................................... 40 
18 
BIBLIOGRAPHY ................................................................................................. 41 
19 
APPENDIX .......................................................................................................... 46 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colorectal, pancreatic, gastroeophageal, appendiceal, small bowel, 
biliary cancer not previously treated with oxaliplatin  
(n = 6 patients) 
Four ml of blood samples are collected at 30 minutes, followed by 1, 
1 hr 45 min, 2 hr, 2 hr 15 min, 3 hr, 4 hr and 24 hr time points after 
the start of [14C]oxaliplatin administration for PK analysis and for 
characterization of DNA adduct repair.  
Starting at least two days but not more than 4 weeks after the initial 
[14C]oxaliplatin microdose administration, patient begins FOLFOX 
with oxaliplatin at a dose of 85 mg/m2 every two weeks.  The initial 
therapeutic dose is administered with a microdose of [14C]oxaliplatin. 
Four ml of blood are collected within 5 minutes prior to initiating the 
dose. 
Four ml of blood are collected within 5 minutes prior to initiation of a 
microdose of [14C]oxaliplatin administered by intravenous (IV) 
infusion over 2 hours. 
Four ml of blood samples are collected at 30 minutes, followed by 
1 hr, 1 hr 45 min, 2 hr, 2 hr 15 min, 3 hr, 4 hr, 24, and 48 hr time 
points after the start of [14C]oxaliplatin administration for PK analysis 
and for characterization of DNA adduct repair.  


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1 
OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 To evaluate the feasibility of [14C]oxaliplatin microdose as a clinical assay to 
predict oxaliplatin exposure 
 
1.2 
Secondary Objectives 
1.2.1 To estimate the degree to which a [14C]oxaliplatin microdose predicts the 
observed pharmacokinetics of standard dose oxaliplatin 
1.2.2 To validate that intrapatient variation of exposure to a [14C]oxaliplatin microdose 
is less than 5%  
1.2.3 To detect the levels of oxaliplatin-DNA adducts induced by oxaliplatin 
microdosing in peripheral blood mononuclear cells (PBMC), and correlate the 
results with patient response and progression free survival on oxaliplatin-based 
chemotherapy 
1.2.4 To develop preliminary safety data of [14C]oxaliplatin microdosing for future 
studies 
2 
BACKGROUND 
The goal of this study is to test the feasibility of using microdose-based diagnostics in 
combination with oxaliplatin-based chemotherapy for personalized cancer treatment.  The key 
hypotheses are that the intravenous infusion of a microdose of [14C]oxaliplatin (~1% of the 
therapeutic dose) will 1) predict the pharmacokinetic exposure to treatment dose oxaliplatin and 
2) that accumulation of the microdose-induced oxaliplatin-DNA damage in surrogate genomic 
DNA from peripheral blood mononuclear cells (PBMCs) will correlate with patient response to 
subsequent full-dose oxaliplatin-based chemotherapy.  In this study, our main objective is to 
collect enough data to evaluate the feasibility of using a [14C]oxaliplatin microdose as a clinical 
assay to predict oxaliplatin exposure.  Key secondary objectives are to assess oxaliplatin-DNA 
adduct biomarkers in PBMCs and assess intrapatient variability of microdose pharmacokinetics.  
Since there will be less than a hundred oxaliplatin-DNA adducts per genome, an ultrasensitive 
measurement technology is required.  Accelerator mass spectrometry (AMS) is the most 
sensitive method available for precise and accurate measurement of drug-DNA adducts.   AMS 
requires a rare isotope label, such as radiocarbon (14C).  For this study we will be dosing 
patients with sub-therapeutic nontoxic doses of 14C-labeled oxaliplatin ([14C]oxaliplatin) that will 
result in minimal radiation exposure to patients (less than one chest X-ray of radiation exposure 
per microdose).     
2.1 
Overview of Cancer Treatment with Platinum Agents 
Platinum (Pt) derivatives are among the most effective and commonly used 
chemotherapeutic drugs for lung, bladder, breast, gynecological, gastrointestinal, testicular, 
hematological and other malignancies. Three platinum-based drugs, cisplatin, carboplatin 
and oxaliplatin, are used for chemotherapy in the U.S.  The pharmacodynamic mechanism 
of platinum chemotherapy is the formation of covalent platinum-DNA adducts (Figure 1).   
 


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Platinum-based drugs preferentially interact with the nucleophilic N7-site of purine bases of 
DNA to form a variety of monoadducts and diadducts (crosslinks) when Pt interacts with 
nucleotides through one or two bonds, respectively [1]. Both intrastrand and interstrand 
diadducts occur in DNA.  The structures of these adducts are well characterized.  These 
adducts induce local perturbations in the DNA double helical structure, which activate the 
proteins that recognize DNA damage [2-4]. The activation of these proteins also results in 
cell cycle arrest, induction of DNA repair processes, and the initiation of programmed cell 
death (Figure 2). Although many details of the mechanisms of action have yet to be 
elucidated, the binding of Pt agents to DNA is well known and is the underling basis for 
measuring Pt-DNA adducts in cells as a potential predictor of patient response to platinum-
based chemotherapy.  Moreover, the efficacy of platinum-based chemotherapy varies 
significantly depending on the types of cancer and individual molecular characteristics.  For 
example, most testicular cancer patients respond to and can be cured with platinum-based 
chemotherapy regimens like BEP (bleomycin, etoposide and cisplatin), even in the presence 
of distant metastasis.  Platinum-based chemotherapy for other types of cancer is less 
effective. 
 
 
 
 
 
 
P t 
N 
H 
H 
N 
O 
O 
O 
O 
* 
DNA 
P 
t 
N 
H 
H 
N
O 
C 
O 
O 
H 
O 
* 
P 
t 
N 
H 
H 
N 
*
Monoadduct 
Diadduct 
+ 
Repaired 
DNA 
[14C]oxaliplatin 
+ 
Figure 1.  Structure of oxaliplatin and formation of oxaliplatin-DNA adducts. The 14C label (*) is 
covalently linked to DNA in both oxaliplatin-DNA monoadducts and diadducts. Only when adducts are 
repaired is the 14C label removed from DNA. AMS measures 14C and, therefore, both monoadducts and 
diadducts in genomic DNA. By measuring the decrease of 14C from genomic DNA, the rate of removal of 
DNA monoadducts and diadducts (DNA repair) can be measured.  


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2.2 
Oxaliplatin 
Oxaliplatin is the third generation of platinum compounds approved for use in cancer 
therapy.  It differs from cisplatin and carboplatin in two significant ways.  First, oxaliplatin’s 
toxicity profile shows a reduction in renal and auditory toxicities, and minimal 
myelosupression.  And second, it does not share the same resistance spectrum as of 
cisplatin and carboplatin.  Oxaliplatin is active in many solid tumors, including colorectal, 
pancreatic, ovarian, lung, and head and neck carcinomas.  Oxaliplatin is presently approved 
for use in combination with 5-fluorouracil (5-FU) and leucovorin (folinic acid).  This treatment 
regimen is indicated for (1) adjuvant treatment of stage III colon cancer in patients who have 
undergone complete resection of the primary tumor and (2) advanced colorectal cancer, (3) 
gastroeophageal 
adenocarcinoma, 
(4) 
pancreatic 
adenocarcinoma, 
(5) 
biliary 
adenocarcinoma, (6) appendiceal adenocarcinoma, (7) duodenal adenocarcinoma.  At the 
present time, the most commonly used combination (modified FOLFOX6) combines 
oxaliplatin with bolus leucovorin and 5-FU followed by a 46-hour infusion of 5-FU [5, 6].   
Oxaliplatin-associated toxicities are cumulative with dose received and are the most 
frequent cause of withdrawal from therapy for those patients that respond well to FOLFOX. 
The major dose limiting toxicity of oxaliplatin is neurotoxicity, which results in treatment 
interruption and discontinuation prior to disease progression in the majority of patients [7].  
The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow the 
development of strategies to manage this side effect in view of the individual patient’s 
clinical situation.  Variation of oxaliplatin in individual patients could affect the accumulation 
Figure 2. Simplified diagram of body/cellular response to platinum
chemotherapy. DNA damage is the critical step in cellular response to platinum
chemotherapy. In this study we will measure DNA damage and repair with a
highly sensitive technology (AMS) and correlate with cellular responsiveness to
platinum chemotherapy.  
Platinum chemotherapy 
Drug metabolism 
Cellular uptake and efflux 
 DNA damage 
Recognition of DNA damage 
Cell cycle arrest 
Apoptosis 
(chemosensitive) 
Cell survival 
(chemoresistant) 
} 
Pre-DNA 
damage 
mechanisms 
} 
Post-DNA 
damage 
mechanisms 


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of oxaliplatin with the nervous system as well as the disposition of oxalate.  Thus, oxaliplatin 
dose optimization has the potential to reduce the development of neurotoxicity in patients 
treated with FOLFOX.   
In phase I studies, the calculated exposure or area under the curve (AUC) of oxaliplatin 
administered at 85 mg/m2 averaged 4.68 µg/mL/hr; however, there was significant inter-
patient variation in AUC (SD 1.40 µg/mL/hr). The metabolism of oxaliplatin occurs in a 
triphasic manner. The initial (T1/2α), second (T1/2β) and terminal (T1/2γ) phase half-lives of 
oxaliplatin are reported to be 25.8 minutes, 16.8  hours and 391 hours, respectively [8, 9]. 
Approximately half of oxaliplatin is excreted in urine within the first 6 hours. Only a small 
fraction of oxaliplatin is excreted at the terminal phase. Because the formation of Pt-DNA 
adducts correlated to the concentration and incubation time of cells with Pt [10], and 
because there is a linear correlation between gross levels of platinum bound to DNA and the 
extent of cytotoxicity [11], it is conceivable that those patients with longer serum half-life of 
Pt may have more cytotoxic effects. We hypothesize that increased metabolism (short half-
life) may be responsible for some cases of resistance to Pt agents. Therefore, a PK study 
may identify those patients with a short half-life of Pt and help design personalized therapy 
studies altering the dose of oxaliplatin to overcome resistance.   
 
2.3 
Resistance to Platinum-based chemotherapy 
Except for testicular cancer, most malignancies have either intrinsic or acquire resistance to 
platinum-based chemotherapy.  Individual aspects of patient and tumor genetic make-ups 
contribute to these drug resistance phenotypes. Numerous studies have been performed to 
explore the mechanisms of resistance to platinum [12]. The chemoresistance mechanisms 
are very complicated and involve more than 700 genes from multiple signaling pathways 
[13]. Studies exploring individual gene alterations have essentially failed to identify clinically 
applicable markers for chemoresistance.  Chemoresistance mechanisms to platinum agents 
can be classified into two major groups (Figure 2): (1) those responsible for the formation of 
Pt-DNA adducts (pre-DNA damage mechanisms), and (2) those involved in cellular 
responses to Pt-DNA adducts (post-damage mechanisms).  
2.3.1 Chemoresistance mechanisms related to the formation of Pt-DNA adducts 
Modulation of uptake and efflux of platinum compounds by cancer cells 
Several studies showed that there is high correlation between decreased Pt 
accumulation and resistance to Pt [14, 15]. Cellular uptake and efflux of Pt drugs appear 
to be mediated by transporters and carriers that are shared with copper [16, 17]. 
However, other studies suggested that passive diffusion plays an important role as well 
[18-21]. Multiple studies showed that resistance to Pt is associated with active efflux of 
drugs. For example members of the multi-drug resistance protein (MRP)-related 
transport proteins are associated with resistance to Pt drugs [22-24]. Cell lines sensitive 
to cisplatin have lower expression of CTR1, a drug efflux transporter [25]. We found 
different carboplatin efflux rates between NSCLC cell lines relative to carboplatin IC50 
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Intracellular inactivation of Platinum Agents 
Glutathione and other thiols can quench the reactivity of platinum-based drugs with 
DNA. In vitro, there is high correlation between intracellular glutathione levels and 
resistance to cisplatin [14, 15, 22]. Overexpression of glutathione S-transferase π 
confers increased resistance to cisplatin in CHO cells [27]. Metallothionein (MT) proteins 
are a family of sulfhydryl-rich proteins that participate in heavy metal binding and 
detoxification. Overexpression of MT-IIA increases resistance to cisplatin [28], while MT-
deficient mice show hypersensitivity to cisplatin [29]. Increased MT was also found in 
bladder tumors from patients who were unsuccessfully treated with cisplatin 
chemotherapy [30]. However, the feasibility of these antioxidant proteins as predictive 
biomarkers of clinical response remains to be demonstrated [31-33]. 
2.3.2 Chemoresistance mechanisms related to Cellular Responses to Pt-DNA Adducts 
Increased DNA Repair 
Increased DNA repair capacity has been well documented to correlate with resistance to 
Pt-based drugs. Testicular cancer is unusually sensitive to Pt, and is deficient in its 
ability to repair DNA [34]. In several Pt-resistant cancer cell lines, high DNA repair 
capacity has been observed [15, 32, 35-37]. 
The mechanisms of DNA repair and its regulation are highly complex. More than a 
dozen proteins participate in the repair of platinum-DNA damage [38].  For example, the 
nucleotide excision repair (NER) complex that forms at a site of DNA damage contains 
at least 15 proteins [39, 40]. The excision repair cross-complementing (ERCC) gene 
family is an important component of NER complex. Increased ERCC1, ERCC2 and XPA 
are associated with resistance to Pt [24, 41], and shortened survival in lung cancer 
patients receiving adjuvant chemotherapy [42]. Similar associations were also observed 
in breast cancer patients who received carboplatin-based chemotherapy [43]. Although 
numerous proteins have been evaluated as biomarkers of response to therapy, only 
ERCC1 has thus far been used as a clinical marker with some success [24]. 
Increased Tolerance of DNA Damage 
There is a significant correlation between increased tolerance of DNA damage and 
resistance to Pt-based drugs [14, 15]. Several mechanisms contribute to increased 
tolerance of DNA damage. Some of these mechanisms involve loss of mismatch repair 
[44], increased DNA replication that bypasses Pt-DNA adducts [45, 46], single 
nucleotide polymorphisms of cell cycle regulators [43], or decreased apoptosis.  
Decreased pro-apoptotic, or increased anti-apoptotic gene expression have been shown 
to participate in resistance to Pt and inhibition of apoptosis [47-49]. 
2.3.3 Summary of Resistance to Platinum-based Chemotherapy 
Owing to the complexity of the above outlined platinum-based drug resistance 
mechanisms, scoring mutations or gene expression changes in a few individual 
pathways is likely to have limited impact on developing biomarker tests for predicting 


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efficacy.  The microdosing approach of this feasibility study provides a strategy for 
obtaining a comprehensive measurement of major resistance factors at play in an 
individual tumor, since the phenotypic in vivo capacity for Pt-DNA adduct formation and 
repair can be directly measured in the patient prior to initiation of platinum-based 
chemotherapy.  
2.4 
Accelerator Mass Spectrometry (AMS) 
AMS was initially developed for geochronology and archaeological research [50, 51]. An 
AMS instrument is an analytical tool that directly quantifies a very rare isotope (e.g. <1 14C 
atom per 109 carbon atoms) in a uniform graphite sample prepared from a biological matrix 
[52, 53].  The extreme sensitivity of AMS is the result of counting 14C atoms directly instead 
of counting 14C radioactive decay events (half-life = 5730 years; 6 x 1011 molecules are 
required for 100 dpm of radioactive decay).  Specificity for 14C atoms occurs by instrument 
design and operation.  AMS has been used in the drug research by our co-investigator Paul 
Henderson, Ph.D. of UC Davis, and his colleagues at Lawrence Livermore National 
Laboratory for the last 15 years. AMS has been used to demonstrate metabolism and 
pharmacokinetics of several dietary and environmental carcinogens [54-56]. Recently, it has 
been used to study the metabolism of cancer drugs such as tamoxifen, doxorubicin and 
carboplatin [57-59]. Compared with the other technologies, the advantage of AMS to detect 
DNA adducts/damage is its high sensitivity and precision. AMS can detect 14C at the 
zeptomole (zmole, 10-21 mole; a few hundred thousand molecules per sample) level per mg 
of carbon with the precision as low as 0.25% [60]. In the application of AMS to cancer 
research, the chemical dose to be administered to patients for AMS analysis can be 
minimized to sub-physiological and sub-toxic doses that are not compatible with other less 
sensitive measurement technologies that require higher doses of chemotherapeutic drugs. 
Furthermore, the specimen size can be reduced to the amounts that can be obtained from 
minimally or non-invasive procedures.  
2.5 
Prediction of Oxaliplatin Exposure 
Optimizing the dose of chemotherapy is essential: If the dose is too low it will be ineffective, 
whereas the toxicity (side-effects) will be intolerable to the patient at excessive doses [61]. 
The standard method of individualizing chemotherapy dose is based on calculated body 
surface area (BSA). However, drug absorption and clearance are influenced by multiple 
other factors, including age, gender, metabolism, disease state, organ function, drug-to-drug 
interactions, genetics, and obesity [62-66].  As a result, there is high variability in the 
systemic chemotherapy drug concentration among patients dosed by BSA, and this 
variability has been demonstrated to be more than 10-fold for many drugs [61, 67].  There is 
a clear unmet medical need to optimize the dosing of chemotherapy drugs compared to 
BSA-based calculations.  
Of the individual drugs in the FOLFOX regimen, 5-FU has been dose optimized in several 
clinical studies, and results in significantly better response and survival rates versus BSA 
dosing [68-70].  For example, in a study involving colorectal cancer patients treated with the 
FOLFOX regimen, the incidence of serious diarrhea was reduced from 12% in the BSA-
dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe 


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mucositis was reduced from 15% to 0.8% [68].  The FOLFOX study also demonstrated an 
improvement in treatment outcomes. Positive response increased from 46% in the BSA-
dosed patients to 70% in the dose-adjusted group. Median progression free survival (PFS) 
and overall survival (OS) both improved by six months in the dose adjusted group. 
The current method (ELISA) for optimizing 5-FU dose is not applicable to oxaliplatin, which 
is in its free form is a chemically reactive compound that is not amenable to antibody-based 
quantitation.  Other common methods for measuring oxaliplatin (ICP-MS and LC-MS) are 
complex and lack the throughput needed for clinical testing.  In this study, we will use liquid 
scintillation counting to assess [14C]oxaliplatin from the plasma ultrafiltrate after 
administration of a microdose.  If successful, we propose to use of a highly sensitive 
accelerator mass spectrometry (AMS) platform to perform assessment of free drug in 
plasma ultrafiltrate from clinical samples after administration of a nanocurie dose of 
[14C]oxaliplatin, which is amenable to high-throughput analysis.  Our goal is to develop a 
[14C]oxaliplatin microdosing assay to optimize the use oxaliplatin, such that the delivered 
AUC is within 10% of the targeted value.  The reduction in variation in achieved dose is 
expected to improve treatment outcome (i.e. response) amongst those who are underdosed, 
and reduce the development of toxicity (especially neurotoxicity) in those who are 
overdosed.  This proposal is the first step in that project, with the aim of demonstrating the 
feasibility of using a microdose of [14C]oxaliplatin to predict the pharmacokinetics of standard 
BSA-dosed oxaliplatin. 
2.6 
Assessment of Microdose-induced Oxaliplatin-DNA damage 
Several studies have confirmed that the levels of drug-DNA adducts directly correlate with 
the outcomes of platinum-based chemotherapy, particularly in peripheral blood mononuclear 
cells (PBMC). After Pt-based chemotherapy, DNA adducts can be detected in multiple 
tissues [10, 71, 72]. The concentration of Pt-DNA adducts correlates to the drug 
concentration and incubation time in cell culture [10]. Decreased Pt-DNA adducts are 
associated with resistance to Pt chemotherapy in cell lines [73]. The levels of DNA adducts, 
as detected by immunohistochemical staining, correlated with response to Pt chemotherapy 
[71, 72]. Those patients with low drug-DNA adducts or increased repair of drug-DNA 
adducts had worse outcomes [74]. Oxaliplatin-DNA adducts have been measured by Pieck 
et al [75] in peripheral blood lymphocytes from 37 patients with a variety of malignancies. In 
patients showing tumor response, adduct levels after 24 and 48 h were significantly higher 
than in nonresponders, indicating that drug-DNA adduct levels in surrogate tissues may 
serve as biomarkers of response. However, the commonly used drug-DNA adduct detection 
methods such as atomic absorption spectroscopy, Southern blot, or immunological detection 
with antibodies, are not sufficiently sensitive for detection of drug-DNA adducts induced by 
microdose concentrations of platinum drugs. Cell lines and patients need to be exposed to 
chemotherapeutic doses (high, toxic concentrations) for a sufficient number of drug-DNA 
adducts to be created for the common adduct detection methods above to be informative 
[76]. Therefore, these traditional approaches can ONLY identify chemoresistance in patients 
AFTER full-dose chemotherapy.    
In this study, we will adopt the highly sensitive technology of AMS for detection of 
microdose-induced platinum-DNA adducts.  We have shown that AMS is about 1000 times 


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more sensitive than the traditional approaches for measuring Pt-DNA adducts [58]. Using 
AMS, we can detect DNA adducts after exposing cell cultures to one microdose of 14C-
oxaliplatin.  Unique to this AMS-based diagnostic assay is that the biomarker is created de-
novo as part of the assay. Consequently, this biomarker assay represents the ultimate 
pharmacodynamic measurement of all aspects of the alkylating drug in the individual 
patient’s tumor.  Given the high concordance of adduct formation in PBMCs with tumor cells, 
we will perform initial analysis through this surrogate tissue.   
As a consequence of administration of a microdose of [14C]oxaliplatin, radiolabelled drug 
molecules interact with DNA to form oxaliplatin-DNA adducts, creating a transient biomarker.  
With prolonged time, free [14C]oxaliplatin is eliminated from serum and cells.  Additionally, 
cells have the capacity to repair oxaliplatin-DNA adducts.  In this study, repeated isolation of 
PBMCs at defined time points will allow for assessment of the kinetics of adduct formation 
and elimination over time.  Using standard techniques for the isolation of genomic DNA and 
processing steps that minimize the loss of label by DNA degradation, [14C]oxaliplatin-DNA 
adducts can be stably isolated.  Using AMS, the oxaliplatin-adduct to DNA mass ratio is 
calculated as the sample specific 14C/C ratio minus the background 14C/C ratio.  Using the 
mass and carbon content of the carrier, the mass of the DNA sample, and the specific 
activity of the [14C]oxaliplatin, an absolute value for the number of 14C atoms per DNA base-
pair can be calculated.  
2.7 
Rationale for the Current Study 
While oxaliplatin-based chemotherapy forms the basis of treatment for patients with various 
gastrointestinal cancers, methods to individualize this treatment based on expected 
response or observed exposure are urgently needed.  For the reasons described in the 
preceding sections, our overall goal is to develop a [14C]oxaliplatin microdosing assay. The 
assay will simultaneously 1) individualize oxaliplatin dosing and 2) predict response (or lack 
thereof) to oxaliplatin-based chemotherapy in individual patients.  As an intermediate step 
toward that goal, the primary aim of this study to test the hypothesis that there is a 
correlation between the oxaliplatin exposure (AUC in plasma) of patients to a microdose and 
exposure of patients to a treatment dose.  If feasible, such an assay would consistently and 
accurately predict treatment dose exposure to oxaliplatin. Furthermore, that assessment of 
DNA adducts formed via the microdose would predict sensitivity and resistance to 
oxaliplatin-based therapy.  Preliminary estimates of these parameters are secondary 
endpoints of this pilot study.    
3 
DRUG INFORMATION 
3.1 
Investigational Drug Information 
[14C]Oxaliplatin Solution is an investigational drug synthesized with a 14C label and 
formulated specifically for this study. The “microdose” consists of a combination of the 
[14C]Oxaliplatin Solution and unlabeled Oxaliplatin for Chemotherapy.  Prior to administration 
as a microdose, the correct dose of [14C]Oxaliplatin Solution and the correct dose of 
unlabeled Oxaliplatin for Chemotherapy must be calculated and prepared to achieve the 
correct patient total oxaliplatin dose and specific radioactivity for this study (see section 
6.3.1 and section 6.4.1). 


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3.1.1 Structural Information 
Oxaliplatin  
 
 
 
 
 
 
14C(* ) is positioned at all carbons in the cyclohexane ring in 14C-oxaliplatin 
Chemical name 
[(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-
O,O')platinum(II) 
Chemical 
abstracts 
registry number 
63121-00-6 
Formula 
C8H14N2O4Pt  
Molecular weight 
397.2858 
NCS Number 
266046 
 
3.1.2 Mechanism of Action 
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active 
derivatives via displacement of the labile oxalate ligand. Several transient reactive 
species are formed, including monoaquo and diaquo DACH platinum, which covalently 
bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. 
Crosslinks are formed between the N7 positions of two adjacent guanines (GG), 
adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide 
(GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-
cycle nonspecific. 
3.1.3  Dosage 
The dose of [14C]oxaliplatin to be administered as a microdose may need to be modified 
(see section 6.3.2) based on the 14C signal in genomic DNA isolated from patients after 
receiving one of the dose levels identified in the dose titration table (Table 1). The dose 
levels being evaluated were identified using the following rationale: Based on our 
ongoing clinical microdosing trial with [14C]carboplatin, the radioactive dose of 
[14C]carboplatin is 107 dpm/kg of patient body weight with a total carboplatin of 1% of 
therapeutic carboplatin with AUC of 6. Our pre-clinical studies with oxaliplatin dosing of 
cell lines indicate that the requirement for [14C]oxaliplatin is about 10 times less than 
[14C]carboplatin. We will begin this study at dose level 1, which we have already 
* 


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demonstrated to be adequate and safe in a single breast cancer patient.  Therefore, the 
start dose (Dose Level 1) of [14C]oxaliplatin will be 2 X 106 dpm/kg  of body weight with 
the total oxaliplatin at 1% of therapeutic dose (Table 1). Based on the 14C signal in 
genomic DNA of peripheral blood mononuclear cells (PBMC) in patients after dosing 
with this dose level 1, the dose will be titrated up or down, if needed, and administered to 
separate patients with the goal of achieving a 14C signal at 10-100 times the background.  
Instructions for preparing the microdose formulation are presented in section 6.3.1. 
 
 
 
 
 
 
 
 
3.1.4 Human Toxicity 
3.1.4.1 Oxaliplatin Chemical Toxicity. 
In this diagnostic feasibility study, patients will receive a small microdose 
of 14C-labelled oxaliplatin (1% of therapeutic dose, or less than 3 mg). We do 
not expect to see any of the clinical side effects associated with standard 
dose oxaliplatin chemotherapy to occur at this low dose. The most common 
side effects of standard dose oxaliplatin chemotherapy are presented in 
section 3.2.3.   
3.1.4.2 Radiation Toxicity Due to 14C-label.  
Patients will receive minimal radiation exposure (<0.02 mSv) with no 
expected toxicity.   
Drug metabolism with 14C-labeled drugs using AMS has been studied in 
healthy volunteers without significant toxicities [77, 78]. We have calculated 
the radiation dose each patient will receive if he/she participates in this trial. 
Most oxaliplatin is excreted in urine. The decline of ultrafilterable platinum 
levels following oxaliplatin administration is triphasic, characterized by two 
relatively short distribution phases (t1/2α of 0.43 hours and t1/2β  of 16.8 hours) 
and a long terminal elimination phase(t1/2γ of 391 hours).   We use 16.8 hours 
as the half-life for calculation.  
For the starting dose, each patient will receive [14C]oxaliplatin at 2 X 106 
dpm/kg of body weight.  
1 µCi = 2.22 x 106 dpm   
If the patient’s body weight is 75 kg, the total radiation dose per microdose 
will be: 
2 X 106 dpm/kg x 75 kg = 1.5 X 108 dpm = 67.6 µCi per microdose. 
Table 1. Dose titration table 
Dose levels 
[14C]oxaliplatin 
(dpm/kg of body weight) 
Total oxaliplatin 
(% of therapeutic dose) 
-1 
1 X 106 
1% 
1 
2 X 106 
1% 
2 
2 X 106 
3% 
3 
10 X 106 
3% 


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1 µCi = 2.22 x 106 dpm x 0.049MeV/disintegration = 108,780 MeV/min = 
108,780 MeV/min X (1.6 x 10-13 joules/Mev) = 1.74 x 10-8 joules/min 
Therefore, each patient will receive: 
67.6 µCi X (1.74 X 10-8 joules/min·µCi) = 1.2 x 10-6 joules/min per microdose. 
If the average body weight is 75 kg, the radiation dose for each microdose 
will be: 
1.2 x 10-6 joules/min person x person / 75 kg body weight = 1.6 x 10-8 
joule/min/kg 
We propose that, after 5 half-lives (84 hours), the [14C]oxaliplatin remaining in 
the body will be negligible. If the patient is continuously exposed to 14C 
radiation without metabolism of [14C]oxaliplatin, the radiation dose will be: 
1.6 x 10-8 joule/min/kg x 60 min/hr x 84 hr (five half-lives) = 7.9 x 10-5 
joules/kg 
1 joule/kg = 1 Sν 
The radiation exposure for each microdose will be 7.9 x 10-5 Sν or 0.079 
mSν.  The radiation exposure for each patient completing both 
microdoses) will be 0.016 mSν.   
If this study ends up at Dose Level 3 (10 X 106 dpm/kg, or 5 times the 
radiation dose used to calculate the above radiation exposure. Table 1), and 
patients undergo both microdose administrations, the radiation exposure will 
be 0.079 mSν x 5 x 2 = 0.79 mSν. 
The annual effective radiation dose equivalent from natural internal sources is 
1.6 mSν per person. The radiation exposure for an abdominal CT scan is 10 
mSv. The radiation exposure to 14C for a patient completing both 
microdoses on this study is 0.016 mSv ÷ 10 mSv = 0.16% of an 
abdominal CT scan. 
Here, we assume that patients are exposed to [14C]oxaliplatin radiation at the 
initial dose for 84 hours without correcting the calculation for reduction of the 
in vivo drug concentration drug by excretion, which makes this a very 
conservative calculation. 
3.1.5 Pharmaceutical Data  
See section 3.2.3 for oxaliplatin pharmaceutical data. 
3.1.6 Administration 
cGMP-certified [14C]oxaliplatin drug product, already in aqueous solution (0.5 
mg/mL), is in sterile, single-use vials that will be stored at the UC Davis 
Investigational Drug Service. This [14C]oxaliplatin is ready to use, and no 
reconstitution is needed. Nuclear medicine and oncology and physicians will 
calculate the [14C]oxaliplatin dose and the unlabeled oxaliplatin dose to obtain a 
patient specific microdose of [14C]oxaliplatin.  When the two drugs are combined 
during infusion, a microdose is created at the desired radiochemical specific 
activity and chemical dose (see section 6.3.1). The [14C]oxaliplatin infusion 
mixture will be prepared by a nuclear medicine technician by adding the 
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oxaliplatin infusion mixture will be prepared by the infusion pharmacy at UC 
Davis Cancer Center by adding the unlabeled oxaliplatin to a separate infusion 
bag containing D5W solution. Both unlabeled and 14C-labeled oxaliplatin will be 
concurrently infused intravenously over 2 hours at the UC Davis Cancer Center 
Infusion Center.  A chemotherapy nurse will administer the unlabeled oxaliplatin.  
A Nuclear Medicine Technologist (CNMT) will administer the 
14C-labeled 
oxaliplatin via Y-site connection to the unlabeled oxaliplatin. 
3.1.7 Storage and Stability  
[14C]oxaliplatin Solution (0.5 mg/mL in water for injection) is packaged as a 
sterile, pyrogen-free, 1.0 mL solution in single use, clear 2 mL glass vials with a 
rubber cap.  It will be stored at the UC Davis Investigational Drug Service in a -
20oC freezer. It is stable when stored at -20oC.  High performance liquid 
chromatography (HPLC) will be performed with the [14C]oxaliplatin at  6-month 
intervals to confirm its stability throughout this trial. 
3.1.8 Manufacture and Formulation 
[14C]oxaliplatin drug substance was manufactured at GE Healthcare using 
organic chemical synthesis, therefore, free of viral or prion contamination. The 
specific activity of the stock [14C]oxaliplatin is 54 mCi/mmol. The purity is 97.7% 
as determined by HPLC. The investigational [14C]oxaliplatin solution (the drug 
product) will be formulated in water for injection and processed at the UC Davis 
cGMP facility for sterile filtration, bacteriostasis/ fungistasis tests, endotoxin 
testing, following cGMP manufacturing procedures. The cGMP [14C]oxaliplatin for 
injection solution is stored at UC Davis Investigational Drug Service and ready for 
the clinical trial. The identity, strength, purity, and stability analyses are 
performed at Moravek Radiochemical Inc (Brea, CA).  Upon thawing, vials will be 
visually inspected for the presence of particulate matter.  Vials with observable 
particulates will be rejected. 
3.2 
Standard of Care Drug Information 
3.2.1 5-Fluorouracil (5-FU)  
a. Description 
1. 5-FU is a fluorinated pyrimidine, which has been modified from the naturally 
occurring product uracil by the addition of a fluoride at position 5. 
2. Molecular Formula: C4H3FN2O2 
3. Molecular Weight: 130.1g/mol  
b. Pharmacology 
Mechanism of Action: 5-FU’s primary mode of action is the inhibition of 
thymidylate synthase which is necessary for both the synthesis and repair of 
DNA. The agent exhibits activity in different phases of the cell cycle based on 
mode of administration. After bolus exposure of 5-FU s-phase cytotoxicity is 
noted. After 24 hours of continuous intravenous infusion G-1 phase cytotoxicity 
has been demonstrated. 
c. Pharmacokinetics 
1. Absorption: Oral 5-FU is incompletely absorbed from the GI tract with highly 
variable rates of bioavailability reported between 0 and 80%. Topical absorption 


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is also minimal with only 2.4% of active drug being absorbed from the 5% 
commercial cream.  
2. Distribution: 5-Fluorouracil has wide ranging distribution to both tissue and 
extracellular fluid. Volume of distribution has been reported between 13-27 liters 
after IV bolus administration. 
3. Metabolism: The metabolism of 5-FU is well known and occurs primarily in the 
liver via non-linear kinetics. The rate limiting step of hepatic breakdown is the 
conversion of 5-fluorouracil to 5-6 dihydrofluorouracil via dihydropyrimidine 
dehydrogenase (DPD). Patients with known DPD deficiency should not be given 
5-FU. 
4. Elimination: the elimination half-life of 5-FU after IV bolus administration has 
been reported to occur within 6-22 minutes. Small amounts of unchanged 5-FU 
are eliminated via the kidney and biliary systems. 
d. Adverse Effects 
1. Human: 
• 
CNS: 
confusion, 
disorientation, 
euphoria, 
nystagmus, 
headache, 
encephalopathy, and peripheral neuropathy 
• Opthalmic: lacrimal duct stenosis, visual changes, lacrimation, and 
photophobia, excessive nasal discharge, reddening of the eyes, blurring of the 
vision 
• Gastrointestinal: stomatitis, esophagopharyngitis, nausea, vomiting, anorexia, 
diarrhea, gastrointestinal ulceration and bleeding 
• Cardiovascular: cardiomyopathy, ischemic chest pain, myocardial ischemia, 
diaphoresis, thrombophlebitis, electrocardiogram changes. 
• Dermatologic: maculopapular rash, alopecia, dry skin, fissuring, hand-foot 
syndrome, nail changes, rash, photosensitivity and vein pigmentation. 
onycholisis, dystrophy, pain and thickening of the nail bed, transverse striations, 
half and half nail changes, loss of nail, paronychial inflammation, and 
hyperpigmentation 
• Hematologic: leucopenia, agranulocytosis, anemia, epistaxis, pancytopenia, 
and thrombocytopenia 
• Immunologic: allergic reactions, anaphylaxis 
2. Pregnancy and lactation: 5-FU is classified as pregnancy category D. 
Teratogenic effects have been demonstrated in animals, however no well 
controlled studies in humans have been performed. In addition, no adequate data 
is available on the use of 5-FU while breast feeding. Women are advised to use 
formula if remaining on treatment.   
e. Administration (Dosing): See treatment plan, section 6.5 
f. Storage/Stability 
1. Compatibility: Store unopen vials at room temperature and protect from light. 
May be diluted in NS or D5W. 


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2. 5-FU is a cytotoxic drug and appropriate procedures for handling, preparing 
and administering the drug should be followed. 
3. When diluted in NS or D5W to a concentration of 1.5 mg/ml in either glass or 
polyvinyl chloride containers 5-FU is stable for 8 weeks at room temperature. In 
ethylene vinyl chloride pumps, 5-FU 10 mg/ml in NS or D5W is stable for 28 days 
at 4—35 degrees C. 
g. How Supplied  
5-FU is available as an IV solution for injection and will be obtained from 
commercial supply. 
3.2.2 Leucovorin Calcium  
a. Description 
1. Leucovorin is a mixture of the diastereoisomers of 5-formyl derivative of 
tetrahydrofolic acid. The active component is the (-)-L-isomer known as 
Citrovorum factor. 
2. Molecular Formula: C20H21CaN7O7 
3. Molecular Weight: 511.51 g/mol 
b. Pharmacology 
Mechanism of Action: During normal processes, thymidylate synthetase forms a 
noncovalent ternary complex with deoxyuridylate (dUMP) and the reduced folate 
cofactor of leucovorin 5,10-methylenetetrahydrofolate (mTHF). The reduced 
folate facilitates the association and disassociation of the complex and the 
formation of thymidylate (dTMP) and dihydrofolate. Fluorouracil inhibits 
thymidylate synthetase through the covalent binding of 5-fluorodeoxyuridine 
monophosphate (FdUMP) and mTHF. The binding of FdUMP is dependent upon 
the intracellular concentration of mTHF. Since l-leucovorin is metabolized to 
mTHF, it increases and stabilizes the binding of FdUMP to thymidylate 
synthetase, thus increasing the cytotoxic effects of fluorouracil. 
c. Pharmacokinetics 
1. Absorption: Oral bioavailability of leucovorin is concentration dependent and 
severely reduced with doses greater than 25 mg. Studies have produced 
bioavailabilities of 97% 75%, and 37% for doses of 25 mg, 50mg and 100mg 
respectively. 
2. Distribution: Leucovorin is rapidly converted to mTHF and distributed widely to 
tissues including the CNS. Distribution is however slowed in the presence of 
methotrexate as this agent competes with bodily tissues for leucovorin, and a 
higher percentage of unchanged drug is excreted in the urine when methotrexate 
is present. 
3. Metabolism: Through the intravenous route the active isomer of leucovorin, l-
leucovorin, is primarily metabolized through hepatic means to mTHF. The d 
isomer is not metabolized nor biologically active. By the oral route leucovorin is 
converted to mTHF primarily by the intestinal mucosa. 
4. Elimination: the d isomer is primarily excreted unchanged in the urine while the 
active form is extensively metabolized by intestinal and hepatic means. 
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d. Adverse Effects 
1. Human toxicity: 
• Gastrointestinal: Toxicity has been studied in combination with 5FU where 
diarrhea, dehydration and stomatitis are all more common with the combination. 
• Immunologic: hypersensitivity and anaphylaxis have been reported  
• Endocrine: hypocalcemia 
2. Pregnancy and Lactation: Leucovorin is classified as FDA pregnancy risk 
category C. No adequate human studies have examined the effects of this drug 
on the fetus. It is not known if leucovorin is excreted into breast milk, and 
therefore mothers receiving the agent should consider alternative modes of 
feeding. 
e. Administration (Dosing): See treatment plan, section 6.5 
f. Storage/Stability 
1. Compatibility Information: leucovorin may be dilute in D5W, D10W, NS, 
Ringer's, or lactated Ringer's solution. 
2. Drug handling and compatibility: leucovorin is not considered as hazardous 
substance and as such may be prepared in a laminar flow hood using aseptic 
technique. 
3. Store dry powder, reconstituted solution and tablets at controlled room 
temperature. Protect from light. When reconstituted with Bacteriostatic Water for 
Injection, the resulting solution must be used within seven days. If reconstituted 
with Sterile Water for Injection, use immediately and discard any unused portion. 
Diluted injections are stable for 24 hours. 
g. How Supplied 
Leucovorin is provided as both a powder and liquid for injection.  Leucovorin is 
commercially available, and will be obtained from commercial supply for this 
study. 
3.2.3 Oxaliplatin (Eloxatin®)  
a. Description 
1. Oxaliplatin is a third generation platinum analog. Oxaliplatin contains a bulky 
carrier ligand, 1,2-diaminocyclohexane (DACH), not present in either cisplatin or 
carboplatin. 
2. Molecular Formula: C8H14N2O4Pt 
3. Molecular Weight: 397.3 g/mol 
b. Pharmacology 
Mechanism of Action: Oxaliplatin is a non-cell cycle specific, alkylating 
antineoplastic agent that inhibits DNA synthesis through the formation of 
Crosslinks between the N7 positions of two adjacent guanines (GG), adjacent 
adenine-guanines (AG), and guanines separated by an intervening nucleotide 
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c. Pharmacokinetics 
1. Absorption: NA 
2. Distribution: oxaliplatin has a protein binding of 70-95% with longer in vitro 
exposure leading to higher protein binding rates. In addition, it has been 
demonstrated approximately 37% of platinum is taken up by erythrocytes. Steady 
state volume of distribution is approximately 35L. 
3. Metabolism: Oxaliplatin is rapidly metabolized in plasma primarily by 
biotransformation. No unchanged oxaliplatin is found 2 hours after administration. 
Oxaliplatin demonstrates no cytochrome P450 metabolism. 17 known 
metabolites of oxaliplatin have been identified, monochloro DACH platinum, 
dichloro DACH platinum, and mono and diaquo DACH platinum, are cytotoxic. 
4. Elimination: Platinum is predominately excreted through the kidney with a 
clearance of 9-17 L/hour. Elimination kinetics are triphasic with alpha, beta, and 
gamma half-lives of approximately 25.8 minutes, 16.8  hours and 391 hours. A 
very small (2%) amount of platinum is excreted in the feces. 
d. Adverse Effects: 
1.  Refer to package insert or manufacturer website for the most complete and up 
to date information on contraindications, warning and precautions, and adverse 
reactions. 
• Cardiovascular: Dyspnea, coughing, hypertension, edema, chest pain  
• Dermatology: injection site reaction  
• Gastrointestinal: Stomatitis, nausea, vomiting, taste alteration, anorexia, 
diarrhea, gastrointestinal reflux 
• Hematologic: leucopenia, agranulocytosis, anemia, epistaxis, pancytopenia, 
and thrombocytopenia, febrile neutopenia 
• Immunologic: allergic reactions, anaphylaxis 
• Hepatic/Metabolic/Laboratory/Renal: hypokalemia, dehydration 
• Neurologic: peripheral neuropathy 
2. Pregnancy and Lactation: Oxaliplatin may cause fetal harm when administered 
to a pregnant woman (FDA pregnancy risk category D). In animal studies, 
oxaliplatin at doses less than one-tenth the recommended human dose based on 
body surface area caused developmental mortality and adversely affected fetal 
growth (decreased fetal weight, delayed ossification). If this drug is used during 
pregnancy or if the patient becomes pregnant while taking this drug, the patient 
should be counseled regarding the potential risks to the fetus. Females of 
childbearing potential should avoid becoming pregnant while receiving treatment 
with oxaliplatin. It is unknown whether oxaliplatin is excreted in breast milk. 
Therefore alternative means to feeding, or delaying treatment should be 
considered. 
e. Administration (Dosing): See treatment plan, section 6.5 
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1. Compatibility: Oxaliplatin is incompatible in a solution with alkaline medications 
or diluents (such as basic solutions of 5-FU) and must not be mixed with these or 
administered simultaneously through the same infusion line. The infusion line 
should be flushed with D5W prior to administration of any concomitant 
medications. Only D5W is acceptable for dilution. Aluminum needles or iv sets 
should not be used as degradation of platinum may occur. 
2. Special Handling: oxaliplatin is a cytotoxic drug and appropriate procedures for 
handling, preparing and administering the drug should be followed. 
3. Store the intact vials at controlled room temperature. Excursions permitted to 
15°C to 30°C (59°F to 86°F), not exceeding 30°C. Reconstituted solution: in 5% 
Dextrose or Water for Injection in the original vial, the solution may be stored for 
up to 48 hours between 2°C to 8° C (36°F-46°F). Infusion solution: after dilution 
in 5% Dextrose in Water, the shelf life is 24 hours at 2°C to 8°C (36°F-46°F). 
g. How Supplied 
1. Oxaliplatin is commercially available and will be obtained from commercial 
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4 
ELIGIBILITY CRITERIA 
4.1 
Inclusion Criteria  
4.1.1 Histologically 
or 
cytologically 
confirmed 
colon, 
rectal, 
pancreatic, 
gastroesophageal, appendiceal, or small bowel adenocarcinoma.  
4.1.2 Intent to treat the patient with a FOLFOX chemotherapy regimen containing 5-
FU, leucovorin, and oxaliplatin according to clinical standard practice. The intent 
should be to dose oxaliplatin at 85 mg/m2 on an every 2 week basis. 
4.1.3 Treatment with any additional FDA-approved biologic agent (i.e. bevacizumab, 
cetuximab, or panitumumab) is allowed according to standard practice.  
4.1.4 Prior radiation or surgery is allowed, but should be finished at least 2 weeks prior 
to study enrollment.  
4.1.5 Any number of prior therapies other than oxaliplatin is allowed.  
4.1.6 Participants must be 18 years or older.  
4.1.7 Zubrod performance status equal to or less than 2 (Karnofsky equal to or greater 
than 50%).  See Appendix A. 
4.1.8 Life expectancy of at least 3 months. 
4.1.9 Participants must have normal organ and marrow function as defined as: 
-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) 
-AST (SGOT) less than or equal to 5 X ULN 
-creatinine less than 1.5 X ULN 
4.1.10 Women of child bearing potential must not be pregnant.  A pre-study pregnancy 
test must be negative. 
4.1.11 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.  
4.1.12 Men must agree to use adequate contraception (barrier method or abstinence) 
prior to study entry and for 30 days after study participation. 
4.1.13 Ability to understand and willing to sign a written informed consent document. 
 
4.2 
Exclusion Criteria 
4.2.1 Prior treatment with oxaliplatin. 
4.2.2 Patients must not receive concomitant radiation. 
4.2.3 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 
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4.2.4 Participants who are pregnant or nursing. 
4.2.5 Participants who are allergic to any platinum agent. 
4.2.6 Participants who have more than Grade 1 peripheral neuropathy. 
5 
DESCRIPTIVE/STRATIFICATION FACTORS 
There is no stratification for the primary analysis of this trial.  However the following data will be 
collected for exploratory analysis of clinical, molecular and treatment factors on outcome. 
• 
Number of prior treatments  
• 
Time from diagnosis 
• 
RAS and BRAF mutation status (if performed) 
• 
ERCC1 expression (if performed) 
6 
STUDY DESIGN AND TREATMENT PLAN 
6.1 
Study Design 
This is a prospective feasibility study of a [14C]oxaliplatin microdose assay to predict 
exposure and sensitivity to oxaliplatin as part of standard-of-care FOLFOX chemotherapy.  
Consenting patients who will be receiving FOLFOX as their treatment for cancer will be 
enrolled.  Patients will receive two [14C]oxaliplatin microdose infusions over the course of the 
study.  The first part of the study is a Phase 0 [14C]oxaliplatin microdose infusion occurring 
over 2 hours and followed by serial blood draws over a 24 hour period for microdose 
pharmacokinetic 
and pharmacodynamic 
analysis 
(on 
surrogate peripheral 
blood 
mononuclear cells).  Between 2 days and 4 weeks after the administration of this phase 0 
microdose, patients will begin FOLFOX therapy according to usual care.  The initial 
treatment oxaliplatin dose will be diluted with the same amount of [14C]oxaliplatin microdose 
as previously administered.  Repeat blood draws for pharmacokinetic assessment of both 
the microdose and therapeutic dose along with pharmacodynamic analysis on PBMCs will 
be performed over 46-48 hours (this last draw is timed for the disconnect visit of the 5-FU 
infusion). 
6.2 
Selection of Patients 
Subjects will be selective from the Medical Oncology clinics at the University of California 
Davis Comprehensive Cancer Center, in-hospital or via outside referral.  The study will be 
presented to potential subjects by the physician with possible assistance from a clinical 
research coordinator.  The enrolling physician is responsible for proposing and explaining 
the study to the prospective subject for the consent process.   
6.3 
Phase 0 [14C]Oxaliplatin Microdose 
6.3.1 Preparation and Administration of [14C]Oxaliplatin Microdose 
The starting dose (Dose Level 1, Table 1) of [14C]oxaliplatin microdose to be 
administered in this study is 2 X 106 dpm/kg  of body weight, with the total dose of both 
unlabeled and 14C-labeled oxaliplatin solution being 1/100th of the planned therapeutic 
dosage (85 mg/m2). Calculations of the therapeutic dose and microdose of oxaliplatin will 
use the Du Bois and Du Bois formula for BSA: 


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BSA (m²) = 0.20247 x Height(m)0.725 x Weight(kg)0.425 
The dose of [14C]oxaliplatin is calculated in the following formula using Dose Level 1 (2 X 
106 dpm/kg, 1% therapeutic dose): 
2 X 106 dpm/kg ÷ (2.22 X 109 dpm/mCi) ÷ 54 mCi/mmol X 397 mg/mmol = 0.0066 
mg/kg 
The patient specific dose of [14C]oxaliplatin will be added to an infusion bag containing 
D5W. Unlabeled oxaliplatin will be added to a separate infusion bag also containing 
D5W. Both treatment dose of unlabeled oxaliplatin and 14C-labeled oxaliplatin will be 
concurrently infused intravenously over 2 hours at the UC Davis Cancer Center Infusion 
Center. When these two infusion bags are concurrently administered to a patient, 
together they achieve a total final oxaliplatin microdose of 1% of the therapeutic dose. A 
chemotherapy nurse will administer the unlabeled oxaliplatin.  A Nuclear Medicine 
Technologist (CNMT) will administer the 14C-labeled oxaliplatin via Y-site connection to 
the unlabeled oxaliplatin. 
As an example, a patient with a height of 1.7 m and a body weight of 75 kg will have a 
BSA of 1.86 m2.  This patient would be planned to receive a therapeutic oxaliplatin dose 
of 158 mg (85 x 1.86).  This patients microdose would then be 1.58 mg of total 
oxaliplatin containing 1.08 mg of unlabeled oxaliplatin for injection and 0.50 mg 
[14C]oxaliplatin solution. The above dosing calculation should be modified as appropriate 
for the other dose levels in Table 1.  Dr. Kim, Dr. Pan or their designees are the only 
authorized prescribers for the microdosing formulation.  If the designee signs the 
pharmacy order form in Dr. Kim or Dr. Pan's absence, the designee must notify Dr. Kim 
or Pan as soon as possible before dosing the patient. 
After the oxaliplatin infusion mixtures are prepared, the shelf-life is 6 hours at room 
temperature [20-25oC] or up to 24 hours under refrigeration [2-8oC].  The oxaliplatin 
microdose infusion mixtures should be administered concurrently through a 120-minute 
intravenous infusion. 
6.3.2 Modification of the radioactive microdose during the study 
We will vary the radioactive dose of [14C]oxaliplatin (dpm/kg) in the patient’s microdose 
by combining the [14C]oxaliplatin with unlabeled oxaliplatin until the desired radioactive 
dose and chemical microdose (total dose at 1/100th of the therapeutic dose) are 
obtained.  This effectively varies the radiochemical specific activity of the microdose 
infusion.  The dose of [14C]oxaliplatin (dpm/kg) for this feasibility study will be determined 
by measuring the 14C associated with genomic DNA isolated from patient’s PBMCs after 
microdosing.  A 14C signal 10-100 times background is acceptable for this study.  Of 
note, the sensitivity for pharmacokinetic analysis is much higher and we do not expect 
dose modification to have any impact on pharmacokinetic feasibility. 
We will start [14C]oxaliplatin at 2 X 106 dpm/kg of body weight, and add unlabeled 
oxaliplatin to 1% of the therapeutic oxaliplatin as calculated based on the dose of 85 
mg/m2. This dose level was demonstrated to be adequate and safe in a single breast 
cancer patient in a prior study.  Two patients will be recruited to this dose level (Dose 


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Level 1).  If the 14C signal in PBMC genomic DNA is sufficient, dose level 1 will be used 
for the rest of the study.  If the 14C signal is insufficient or too high, the dose level will be 
titrated up or down, respectively, based on the 14C signal as outlined in Table 1, and 
administered to two additional patients per dose level until a sufficient 14C signal is 
obtained.  If no 14C signal can be detected in the genomic DNA at Level 3, no further 
escalation will be performed. 
6.3.3 Sample Collection Schedule 
Blood will be collected for pharmacokinetic and pharmacodynamic analysis according to 
the schedule in Table 2.  See section 10.1.1 for sample processing. 
 
6.4 
Cycle 1 [14C]Oxaliplatin Microdose Concurrent with FOLFOX 
6.4.1 Preparation and Administration of [14C]Oxaliplatin Microdose with Therapeutic 
Oxaliplatin dose. 
The [14C]Oxaliplatin infusion mixture in D5W will be prepared as described in Section 
6.3.1. After this infusion mixture is prepared, the shelf-life is 6 hours at room temperature 
[20-25 oC] or up to 24 hours under refrigeration [2-8 oC].  The treatment dose of 
oxaliplatin should also be prepared in a separate infusion bag containing D5W. Both 
treatment dose of unlabeled oxaliplatin and 14C-labeled oxaliplatin will be concurrently 
infused intravenously over 2 hours at the UC Davis Cancer Center Infusion Center.  A 
chemotherapy nurse will administer the unlabeled oxaliplatin.  A Nuclear Medicine 
Technologist (CNMT) will administer the 14C-labeled oxaliplatin via Y-site connection to 
the unlabeled oxaliplatin. 
6.4.2 Sample Collection Schedule 
Blood will be collected for pharmacokinetic and pharmacodynamic analysis according to 
the schedule in Table 3.  See section 10.1.1 for sample processing. 
 
 
Table 2. Time Points of Blood Collection for PK Assessment after Phase 0 Microdose 
Sample 
Number 
Scheduled time points relative to [14C]oxaliplatin administration 
Day 
Scheduled time 
Description 
1 
1 
0-5 min predose 
Pre-dose 
2 
1 
30 minutes (±5 minutes) 
Post-dose 
3 
1 
1 hr (±10 minutes) 
Post-dose 
4 
1 
1 hr 45 min  (±10 minutes) 
Post-dose 
5 
1 
2 hr (±10 minutes) 
Post-dose 
6 
1 
2 hr 15 min (±10 minutes) 
Post-dose 
7 
1 
3 hr (±10 minutes) 
Post-dose 
8 
1 
4 hr (±60 minutes) 
Post-dose 
9 
1 
24 hr (±60 minutes) 
Post-dose 


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6.5 
FOLFOX Treatment 
6.5.1 Premedication and Supportive Care 
Premedication associated with standard drug administration and supportive care 
(including anti-diarrheals, antibiotics, diuretics or other medications) should be 
given according to institutional standards.   
6.5.2 FOLFOX 
Patients will be treated with modified FOLFOX6 according to the following initial 
schedule for cycle 1.  Cycle length is defined as 14 days.  Modifications to cycle 
1 treatment (other than oxaliplatin dose) may be allowed, but discussion with the 
primary investigator is required.  Modifications to dosing beyond cycle 1 are at 
the discretion of the treating investigator according to usual medical practice.  
 
Table 4. Modified FOLFOX6 Chemotherapy Regimen 
Agent 
Dose 
Route 
Day 
Schedule 
Leucovorin 
Calcium* 
400 mg/m2 
IV 
1 
Every 14 days 
5-FU 
400 mg/m2 
Bolus IV 
1 
Every 14 days 
Oxaliplatin 
85 mg/m2 
IV over 2 hours 
1 
Every 14 days 
5-FU 
2400 mg/m2 
IV over 46-48 hours 
via ambulatory 
infusion pump 
1-2 
Every 14 days 
*In the event of a leucovorin calcium shortage, the dosage may be reduced to 20 mg/m2 
or 200 mg/m2 racemic levoleucovorin may be substituted. Leucovorin may be infused 
concurrently with oxaliplatin (via separate infusion lines). 
** Note during cycle 1 only, Oxaliplatin infusion will contain [14C]Oxaliplatin Microdose as 
described in section 6.4.1 
 
 
 
Table 3. Time Points of Blood Collection for oxaliplatin PK Assessment after Therapeutic-
Associated Microdose 
Sample 
Number 
Scheduled time points relative to [14C]oxaliplatin administration 
Day 
Scheduled time 
Description 
1 
1 
0-5 min predose 
Pre-dose 
2 
1 
30 min (±5 minutes) 
Post-dose 
3 
1 
1 hr (±10 minutes) 
Post-dose 
4 
1 
1 hr 45 minutes (±10 minutes) 
Post-dose 
5 
1 
2 hr (±10 minutes) 
Post-dose 
6 
1 
2 hr 15 min (±10 minutes) 
Post-dose 
7 
1 
3 hr (±10 minutes) 
Post-dose 
8 
1 
4 hr (±60 minutes) 
Post-dose 
9 
1 
24 hr (±60 minutes) 
Post-dose 
10 
2 
48 hr (± two hours) 
Post-dose 


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6.6 
Follow Up Period 
Patients will remain on study until progression of disease or until any of the criteria in 
section 6.7 are met.  If an intermittent oxaliplatin strategy is chosen, the time of progression 
will be defined as progression after the first reintroduction of oxaliplatin, as has previously 
been defined [79, 80]. 
6.7 
Criteria for Discontinuation  
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
• 
Intercurrent illness 
• 
Occurrence of an unacceptable adverse event 
• 
A treatment delay between phase 0 microdose and FOLFOX treatment of greater 
than 28 days for any reason 
• 
Patient request 
• 
Protocol violations 
• 
Non-compliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 
• 
General or specific changes in the patient’s condition unacceptable for further 
treatment in the judgment of the investigator 
7 
EVENTS TO BE MONITORED AND DOSE MODIFICATIONS  
7.1 
Safety Assessments 
Safety will be monitored by performing a physical examination and assessing vital signs, 
performance status, laboratory evaluations, and collecting the adverse events.  Because the 
investigational intervention is not expected to result in any significant toxicity, study safety 
evaluations will be performed at baseline, following each microdose administration, and for 
14 days following microdose administration or until all attributed adverse events from the 
microdose have resolved, whichever is later.  The timing of safety assessments after this 
period is at the discretion of the treating investigator according to good medical practice.  
For details on adverse event collection and reporting, refer to Section 7.2.  
7.1.1 Physical Examination 
A baseline comprehensive physical examination will be performed which must comprise 
a total body examination (general appearance, skin, neck, including thyroid, eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, and extremity). A 
comprehensive physical examination will be performed at the Pre-Study visit and at the 
Cycle 2 - Day 1 study visit. A symptom-directed physical examination will be performed 
on the Cycle 1 - Day 1 study visit and at any time during the study, as clinically indicated. 
7.1.2 Vital Signs 
Vital sign assessment consists of height (pre-study visit only), pulse, blood pressure, 
respiration rate, temperature and weight. Blood pressure, pulse and respiration rate 
should be measured on patients after at least 3 minutes in the sitting position.   


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7.1.3 Performance Status 
Zubrod (ECOG) Performance Status (Appendix A) will be determined by the treating 
Investigator at each physical examination visit. 
7.1.4 Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils; lymphocytes; monocytes; eosinophils; basophils), and platelet count will be 
measured Pre-Study, on day 1 of Phase 0 Microdose, on Cycle 1 - Day 1, and Cycle 2 
Day 1.  Testing must be performed within 14 days of registration, and within 72 hours of 
subsequent time points.   
7.1.5 Serum chemistry 
Blood urea nitrogen (BUN), creatinine, total bilirubin, AST, ALT, alkaline phosphatase, 
sodium, potassium, chloride, calcium, glucose, total protein, and albumin, will be 
measured Pre-Study, on day 1 of Phase 0 Microdose, on Cycle 1 - Day 1, and Cycle 2 
Day 1.  Testing must be performed within 14 days of registration, and within 72 hours of 
subsequent time points.   
7.1.6 Pregnancy Test 
All pre-menopausal women who are not surgically sterile will have a urine pregnancy 
test at the Pre-Study visit and a urine pregnancy test as clinically indicated. A positive 
urine pregnancy test requires a serum β-hCG to be performed to confirm this result. 
7.2 
Adverse Events 
Because the investigational intervention is not expected to result in any significant adverse 
events, adverse event evaluations will be performed at baseline, following each microdose 
administration, and for 14 days following microdose administration or until all attributed 
adverse events from the microdose have resolved, whichever is later.  Adverse events will 
be graded accorded to the NCI Common Terminology Criteria for Adverse Events Version 
4.0 (CTCAE v4.0).  If CTCAE grading does not exist for an adverse event, the severity of 
mild, moderate, severe, and life-threatening, or grades 1 - 4, will be used.  Upon completion 
of the adverse event assessment window, patients will be followed for efficacy only (see 
section 7.3) until the follow up criteria in section 6.6 are met.  
7.2.1 Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product 
whether or not it is related to the medicinal product.  This includes any newly occurring 
event, or a previous condition that has increased in severity or frequency since the 
administration of study drug. 
For this protocol an abnormal laboratory value will not be assessed as an AE unless that 
value leads to discontinuation or delay in treatment, dose modification, therapeutic 


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intervention, or is considered by the investigator to be a clinically significant change from 
baseline. 
7.2.2 Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification below on planned hospitalizations in Section 6.3). 
 
Results in persistent or significant disability or incapacity.  (Disability is defined as 
a substantial disruption of a person’s ability to conduct normal life functions). 
 
Is a congenital anomaly/birth defect. 
 
Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the 
patient, require medical or surgical intervention to prevent one of the outcomes 
listed above, or involves suspected transmission via a medicinal product of an 
infectious agent.    
• 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
• 
With respect to the suspected transmission via a medicinal product of an 
infectious agent; any organism, virus, or infectious particle (eg, prion 
protein transmitting Transmissible Spongiform Encephalopathy), whether 
pathogenic or non-pathogenic, is considered an infectious agent.   
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) 
of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache).  This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above and is usually 
associated with events that pose a threat to a patient’s life or ability to function.  A 
severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  For 
example, a white blood cell count of 1000/microL to less than 2000 is considered Grade 
3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
7.2.3 Reporting Requirements 
In addition to completing appropriate demographic and suspect medication information, 
the report should include the following information within the Event Description of the 
Medwatch Form 3500A 


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• 
Treatment regimen (dosing, frequency, combination therapy) 
• 
Protocol description (include number if assigned) 
• 
Description of event, severity, treatment, and outcome, if known 
• 
Supportive diagnostic and laboratory results 
• 
Investigator’s assessment of the relationship of the SAE to each investigational 
product and suspect medication 
7.2.3.1 Follow-up information 
Additional information may be added to a previously submitted report 
by any of the following methods: 
• 
Adding to the original Medwatch Form 3500A and submitting it 
as follow-up 
• 
Adding supplementary summary information and submitting it 
as follow-up with the original Medwatch Form 3500A 
• 
Summarizing new information and faxing it with a cover letter 
including subject identifiers (ie, DOB, initials, subject number), 
protocol description and number, suspect drug, brief adverse 
event description, and notation that additional or follow-up 
information is being submitted 
7.2.4 Safety Reporting Requirements for IND  
For Investigator Sponsored IND Studies there are some additional reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR 312.32.  
Sponsor-investigators of studies conducted under an IND must comply with the following 
safety reporting requirements: 
7.2.4.1 Expedited IND Safety Reports 
The Sponsor-Investigator is required to report all serious, 
unexpected and related adverse events directly to the FDA on a 
MEDWATCH Form 3500A within 7 (if fatal or life-threatening) or 15 
calendar days of first awareness.  
The Sponsor-Investigator must report in an IND safety report any 
suspected adverse reaction that is both serious and unexpected (21 
CFR 312.32). Before submitting this report, the sponsor needs to 
ensure that the event meets all three of the definitions contained in 
the requirement: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
If the adverse event does not meet all three of the definitions, it 
should not be submitted as an expedited IND safety report to the 
FDA.  


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The timeframe for submitting an IND safety report to FDA is no later 
than 15 calendar days after the investigator determines that the 
suspected adverse event or other information qualifies for reporting.  
Any fatal or life-threatening serious, unexpected and related 
adverse event must be reported to no later than 7 calendar days 
after initial awareness.  Sponsor-Investigators should initially notify 
FDA by telephone or facsimile transmission. Other means of rapid 
communication (e.g., email) may also be used, if prior to 
transmission, the Project Manager in the FDA review division that 
has responsibility for review of the IND confirms that other means of 
rapid transmission are acceptable. 
Any serious, unexpected and related adverse event that is not fatal 
or life-threatening must be reported to FDA no later than 15 
calendar days after initial awareness. 
The Sponsor-Investigator must comply with any applicable 
requirements related to the reporting of SAEs involving his/her 
subjects to the IRB that approved the study. 
7.2.4.2 IND Annual Reports 
In accordance with the regulation 21 CFR 312.33, the Sponsor-
Investigator shall within 60 days of the anniversary date that the IND 
went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR 
312.33 for a list of the elements required for the annual report.   
7.3 
Efficacy Assessments 
For the purposes of this study, screening tumor assessments using CT of the 
chest/abdomen/pelvis and other areas of known disease or newly suspected disease should 
be performed within 28 days prior to registration. Scans of the abdomen, pelvis and other 
areas of the body may be done with MRI instead of CT, but evaluation of the chest should 
be done with CT.  CT scans should be performed with iodinated IV contrast and MRI scans 
with IV gadolinium chelate unless there is a medical contraindication to contrast. If iodinated 
IV contrast is contraindicated, chest CT should be done without IV contrast.  The CT 
component of a combined PET/CT may be used as long as the slice thickness is < 5 mm. 
For the purposes of this study, patients with radiographically measurable disease at 
baseline should be re-evaluated for response every 8 weeks (+/- 1 week) for 6 months and 
then every 12 weeks (+/- 2 weeks) thereafter.  The interval in imaging may be changed after 
discussion with the principal investigator.  Response and progression will be evaluated in 
this study using the international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.  
Please see Appendix C for RECIST 1.1 criteria.   


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7.4 
Dose Modifications 
After initiation of treatment in Cycle 1 all dose modifications and delays are at the discretion 
of the treating investigator according to best medical practices.   
8 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
8.1 
Criteria for Evaluation 
Evaluable patients will include eligible subjects who receive both the phase 0 and FOLFOX-
integrated microdose and have samples collected at least 80% of time points.  All patients 
who receive any component of microdose will be followed for toxicity, but any patient not 
completing both microdose administrations and 80% of blood samples will be replaced.  
8.2 
Endpoint Definitions 
8.2.1 Primary Endpoint 
The primary endpoint is the feasibility of assessing therapeutic pharmacokinetic (PK) 
parameters of the therapeutic dose using the microdose in evaluable patients.  For the 
purposes of this pilot study, this assessment will be considered feasible if the area under 
the curve extrapolated to infinity (AUC0-∞) of the microdose and the therapeutic dose are 
within 2-fold of each other when normalized for differences in dose with a 95% 
confidence interval.   
8.2.1.1 Justification of the primary endpoint 
Prior microdosing work suggests that a close relationship between multiple 
microdose and full dose pharmacokinetic parameters including t1/2 and AUC 
can be observed [77].  In this study, we have chosen to focus on total 
exposure to treatment as total exposure is related to the primary dose limiting 
toxicity of oxaliplatin treatment (i.e. peripheral neuropathy) [81].  While a 
close relationship will be required for final development, a relationship within 
2-fold will provide sufficient preliminary data to suggest that further 
development and optimization of the assay will be warranted.      
8.2.2 Secondary Endpoints 
Secondary endpoints include: 
8.2.2.1 Assessment of other PK parameters (e.g. Cmax, tmax, t1/2, CL) of the phase 0 
microdose compared to the therapeutic dose. 
8.2.2.2 Comparison of the PK parameters of the phase 0 microdose to the FOLFOX-
integrated microdose. 
8.2.2.3 The association of oxaliplatin-DNA adducts (see section 10.3) and tumor 
response by RECIST 1.1 (see Appendix C).  
8.2.2.4 The association of oxaliplatin-DNA adducts (see section 10.3) and duration 
of disease control (see Appendix C).  
8.2.2.5 Safety according to the Common Terminology Criteria for Adverse Events 
version 4 (see section 7.2).   


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9 
STUDY CALENDAR 
 
PERIOD 
Pre-
Studya 
Phase 0 Microdose 
Cycle 1 + Microdose 
Ongoing Treatment 
Off Study 
 
 
Day 1 
Day 2 
Day 1 
Day 2 
Day 3 
Cycle 2, 
Day 1 
Ongoing 
Treatment 
 
Safety Assessments.b  See Section 7.1 
History & Physical Exam 
X 
 
 
X 
 
 
X 
* 
 
Vital Signs 
X 
X 
 
X 
 
 
X 
* 
 
Performance Status 
X 
 
 
X 
 
 
X 
 
 
Hematology 
X 
X 
 
X 
 
 
X 
* 
 
Serum Chemistries 
X 
X 
 
X 
 
 
X 
* 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Adverse Events. See Section 7.2 
Adverse Events 
 
X------------------------------------------------------------------------------X 
 
 
Efficacy Assessments. See Section 7.3 
Imaging Studies 
X 
 
 
 
 
 
 
Xc 
X 
Treatments. See Section 6. 
[14C]Oxaliplatin Microdose 
 
X 
 
X 
 
 
 
 
 
FOLFOX 
 
 
 
X-----------------------------X 
X 
* 
 
Biologic Agent, if appropriate 
 
 
 
 
 
X 
 
* 
 
Correlative Studies.  See Sections 6.3.3, 6.4.2 and 10.1 
Plasma Pharmacokinetics 
 
X 
X 
X 
X 
X 
 
 
 
PBMCs 
 
X 
X 
X 
X 
X 
 
 
 
a Pre-study assessments within 14 days before registration, except for imaging studies within 28 days of registration 
b All on study safety assessments may be performed +/- 72 hours of the indicated timepoint 
c Every 8 weeks (+/- 1 week) for 6 months then every 12 weeks (+/- 2 weeks) until progression. Required only in patients with measurable 
disease at baseline. 
* After Cycle 2, Day 1 and resolution of all microdose-associated toxicities, all safety assessments and treatments are at the discretion of the 
treating investigator according to good medical practice.  


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10 SPECIAL INSTRUCTIONS 
10.1 Specimen Collection, Storage, Shipping and Submission Requirements 
10.1.1 Collection Method and Storage   
One 8-ml blood specimen will be collected into a BD Vacutainer CPTTM tube with 
sodium heparin (Becton Dickinson products # 362753) through an indwelling temporary 
venous catheter at the time points described in Table 2 and Table 3. The tube will be 
gently inverted several times to ensure mixing with heparin anticoagulant. The tube will 
be immediately put on ice. To isolate plasma, the tubes are centrifuged at room 
temperature in a horizon rotor for 25 minutes at 1600 X g. After centrifugation, plasma is 
located at the top of the specimen (Figure 3), and will be transferred to two 
polypropylene cryogenic vials.  The vials will be labeled with patient’s identification 
information and stored at or below -70oC until shipping. After collection of all of the 
specimens from the same patients, the 14C content in plasma is determined by liquid 
scintillation count. The oxaliplatin concentration is calculated based on the 14C content in 
the plasma specimens. 
Figure 3. Centrifugation to separate Plasma and Mononuclear Cells in Peripheral Blood 
  
After most of the plasma is removed for PK study, PBMC will be transferred to another 
tube, washed twice with ice-cold phosphate-buffered solution (PBS) with 2% fetal calf 
serum. DNA will be extracted from PBMC as described before [67], and sent to 
Accelerated Medical Diagnostics and LLNL for Pt-DNA adduct measurement. 
10.1.2 Shipping and Submission Requirements   
The peripheral blood specimens can be immediately kept at 4oC or on ice up to four 
hours before the plasma and PBMC are separated. Plasma will then be stored at –70oC 
freezer until PK studies. PBMC will be used for DNA extraction immediately after 
separation.  
 
 


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10.2 Pharmacokinetics 
10.2.1 Specimens & Collection Frequency 
Blood specimens will be collected at the time points outlined in Table 2 and Table 3. 
Plasma will be used for PK assessment. Since a very small fraction of oxaliplatin is 
metabolized at the terminal phase, we will not determine the terminal half-lives if they 
are longer than 24 hours. 
10.2.2 Analysis Method 
The 14C content in plasma is measured by liquid scintillation counting. The carboplatin 
concentration is calculated based on the 14C content in the plasma specimens.  Cmax, 
t1/2, and AUC of plasma carboplatin will be calculated for the carboplatin microdose 
setting and reported.  
10.3 Assessment of Platinum-DNA Adducts in PBMCs 
DNA containing [14C]oxaliplatin-DNA adducts will be extracted from PBMCs (collected 
according to section 10.1) at Accelerated Medical Diagnostics as described previously [58, 
82]. The DNA samples will be quantified by micro spectrophotometry, aliquoted and then 
delivered to Lawrence Livermore National Laboratory (LLNL) at 7000 E. Avenue, Livermore, 
CA 94550 for AMS analysis.  Oxaliplatin-DNA adduct frequency levels (1-100 adducts per 
108 nucleotides) will be reported. Comparison of oxaliplaton-DNA adduct levels in PBMC’s 
to response data will be as described in section 11.2. 
11 STATISTICAL CONSIDERATIONS 
11.1 Statistical Design 
This is a prospective feasibility diagnostic study of a phase 0 microdose of [14C]oxaliplatin to 
ascertain whether there is sufficient promise to proceed for further study.   
11.2 Analysis Plan 
11.2.1 Primary Analyses 
For the primary endpoint of feasibility is defined in section 8.2.1.  We will correlate dose 
normalized AUC0-∞ parameters from phase 0 microdosing with parameters from the 
therapeutic dose of oxaliplatin for evaluable patients (the criteria for evaluation are listed 
in section 8.1). While assessment of PK feasibility is the primary endpoint of this study, 
we will use the totality of the data, including assessment of DNA adduct formation in 
PBMCs to determine the future development of this assay.   
11.2.2 Secondary Analyses 
Given the small number of patients included in this pilot study, all secondary analyses 
will be considered hypothesis generating for the design of future confirmatory study. 
11.2.2.1 For secondary endpoint 8.2.2.1, we will correlate PK parameters 
from microdosing with parameters from therapeutic doses of 
oxaliplatin. All parameters will be normalized for dose. We will 
present descriptive summaries (scatterplots, tables, mean, SD, 


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correlation coefficient) of the relationship between the two sets of 
parameters. 
11.2.2.2 For secondary endpoint 8.2.2.2, we will correlate PK parameters 
from phase 0 microdosing with parameters from FOLFOX-integrated 
microdosing of oxaliplatin. We will present descriptive summaries 
(scatterplots, tables, mean, SD, correlation coefficient) of the 
relationship between the two sets of parameters. 
11.2.2.3 For secondary endpoint 8.2.2.3 and 8.2.2.4, we will characterize the 
repair of DNA adducts in PBMC, using descriptive statistics 
(graphical summaries, mean, SD, box plots). Response rate and 
duration of disease control (DDC) will be measured according to 
RECIST 1.1 (Appendix C). The DDC is equivalent to progression 
free survival if an intermittent oxaliplatin strategy is not employed.  
Progression free survival will be calculated from the date of 
enrollment to the date of first objective evidence of radiographic 
progression (soft tissue or bone lesion) or date of death due to any 
cause, whichever occurs first. If an intermittent oxaliplatin strategy is 
chosen, we will define DDC as the addition of the initial PFS and the 
PFS of the reintroduction, except in case of progression at the first 
evaluation after FOLFOX reintroduction.  Radiological assessment 
by the treating Investigator will be the primary report in this analysis.  
We hypothesize that higher levels of DNA repair will be associated 
with non-response and shorter duration of disease control.  
11.2.2.4 For secondary endpoint 8.2.2.5, we will assess toxicity to both 
micordoses of [14C]oxaliplatin. Toxicities potentially related to 
[14C]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. Descriptive statistics will be used rather than 
inferential statistics. 
11.3 Sample Size  
The number of subjects required to provide 80% probability that a 95% CI for the ratio of 
geometric means of full dose and micro dose PK parameters is within 2 fold (i.e., from 0.5 to 
2) depends on the coefficient of variation (CV) of the ratio of the parameters, which depends 
on the CV of each parameter and the within-person correlation between the full dose and 
micro dose parameters (on a log scale).   According to the Lappin et al. [77], CVs for t1/2 
were in the 0.3-0.5 range for diazepam and midazolam (which had good concordance 
between doses as well as adequate bioavailability).  With these specifications, a sample 
size of 6 patients receiving both full- and micro-doses is sufficient. 
12 REGISTRATION GUIDELINES 
Once signed, informed consent has been obtained; patients will be entered on study.  To 
register a patient, the data manager must complete the Eligibility Checklist (Appendix B). The 
data coordinator will register the patient onto the study and assign a unique patient number.    


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13 DATA SUBMISSION  
13.1 Confidentiality of Records   
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is 
alive) at the end of their scheduled study period. 
The data collection system (eVELOS) for this study uses built-in security features to encrypt 
all data, preventing unauthorized access to confidential participant information.  Access to 
the system is controlled by a sequence of individually assigned user identification codes and 
passwords, made available only to authorized personnel who have completed prerequisite 
training. 
13.2 Patient Consent Form 
At the time of registration, three signed and dated copies of the patient Informed Consent 
form with the Human Rights must be available (for patient, patient's medical chart and one 
for UC Davis).   
13.3 Registration Eligibility Worksheet   
At the time of registration, the information requested on Eligibility Checklist will be submitted 
to the Protocol Coordinator.  
13.4 Data Collection Forms and Submission Schedule 
All data will be collected using the UCD Database System (eVELOS) forms.  All data forms 
will be completed, submitted and processed in accordance with UCD CTSU policies.  
13.5 Database Management and Quality Control 
Quality assurance audits of select patients and source documents may be conducted by the 
UC Davis Cancer Center Quality Assurance Committee as outlined in the UC Davis Cancer 
Center Data and Safety Monitoring plan. 
Quality control will be maintained by the CTSU Quality Assurance team according to CTSU 
policy. 


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14 MINORITIES AND WOMEN STATEMENT 
Recruitment is open to all minorities. Although distributions may vary by disease type, our 
recruitment procedures have been developed to enroll patients who are representative of the 
respective target population.   
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Ethical Conduct of the Study 
This study will be conducted in accordance with the Declaration of Helsinki and Good 
Clinical Practice (GCP) according to (International Conference on Harmonization) ICH 
guidelines. Specifically, the study will be conducted under a protocol reviewed by an IRB; 
the study will be conducted by scientifically and medically qualified persons; the benefits of 
the study are in proportion to the risks; the rights and welfare of the subjects will be 
respected; the physicians conducting the study do not find the hazards to outweigh the 
potential benefits; and each subject will give his or her written, informed consent before any 
protocol-driven tests or evaluations are performed.  
Essential clinical documents will be maintained to demonstrate the validity of the study and 
the integrity of the data collected. Master files will be established at the beginning of the 
study, maintained for the duration of the study and retained according to the appropriate 
regulations. 
15.2 Informed Consent Procedures  
Informed consent will be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent will 
be documented in the patient source documents. 
All patients will have signed an informed consent for participation in research activities in 
accord with all institutional, NCI and Federal regulations, and will have been given a copy of 
the Experimental Subject's Bill of Rights.  
16 DATA AND SAFETY MONITORING 
This protocol is also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety 
Monitoring Plan. The UCDCC is committed to pursuing high-quality patient-oriented clinical 
research and has established mechanisms to ensure both scientific rigor and patient safety in 
the conduct of clinical research studies. The UCDCC relies on a multi-tiered committee system 
that reviews and monitors all cancer clinical trials and ensures the safety of its participants, in 
compliance with institutional and federal requirements on adverse event (AE) reporting, 
verification of data accuracy, and adherence to protocol eligibility requirements, treatment 
guidelines, and related matters. The Scientific Review Committee (SRC) assumes overall 
oversight of cancer studies, with assistance and input from two independent, but interacting, 
committees: the Quality Assurance Committee and the Data Safety Monitoring Committee. A 
multi-level review system strengthens the ability of the UCDCC to fulfill its mission in conducting 
high quality clinical cancer research. 


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As per University of California Davis Cancer Center (UCDCC) Clinical Trials Support Unit 
(CTSU) SOP AM 506: Protocol Specific Meetings, the principal investigator (PI), clinical 
research coordinator (CRC), and the clinical research nurse meet at least monthly for ongoing 
study information, to discuss patient data and adverse events and to determine if dose 
escalation is warranted, when applicable.   
According to the UCDCC Data and Safety Monitoring Plan (DSMP), any new serious adverse 
events related to the drugs being used on this trial are reviewed monthly by the UCDCC Data 
and Safety Monitoring Committee (DSMC) and any applicable changes to the study are 
recommended to the PI, if necessary. 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety 
Monitoring Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The DSMB 
is responsible for reviewing study accrual logs, adverse event information and dose escalation 
meeting minutes (where applicable) to ensure subject safety and compliance with protocol 
defined guidelines. 
17 PATHOLOGY REVIEW 
All patients will have malignancy confirmed by review of their biopsy specimens by the 
Department of Pathology at the University of California at Davis. 
 
 


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58. 
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77. 
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19 APPENDIX 
Appendix A – ECOG/Zubrod Performance Status Scale 
 
 
ECOG/Zubrod Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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Appendix B – Eligibility Worksheet 
 
 
Patient Name _____________________________ MRN ______________________________ 
 
Each question must be answered appropriately for a patient to be considered eligible for 
registration. Patients are eligible if they meet the following criteria (all answers must be “yes”).   
If the criteria is not applicable answer “yes.” 
 
YES 
NO 
CRITERIA 
 
 
Histologically or cytologically confirmed colon, rectal, pancreatic, 
gastroesophageal, appendiceal, or small bowel adenocarcinoma 
 
 
Intent to treat with a FOLFOX chemotherapy regimen containing oxaliplatin at 85 mg/m2 
on an every 2 week basis. 
 
 
Prior radiation or surgery is allowed, but should be finished at least 2 weeks prior to study 
enrollment.  
 
 
18 years or older. 
 
 
Zubrod performance status equal to or less than 2. See Appendix A 
 
 
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) 
 
 
AST (SGOT) 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. 
 
 
Able to understand and willing to sign a written informed consent document. 
 
 
No prior oxaliplatin. 
 
 
No plans to receive concomitant radiation. 
 
 
No 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. 
 
 
Not allergic to any platinum agent. 
 
 
No more than Grade 1 peripheral neuropathy. 
 
 


UCDCC#255 
Protocol Version: 4.0 (07-14-2017)   
 
48 
Eligibility Checklist Completed By: _________________________________  Date: _________ 
 
Appendix C - Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
administration of the [14C]oxaliplatin microdose. 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of FOLFOX therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  Patients 
who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area are not considered 
measurable unless they have been demonstrated to progress prior to their selection as a 
measurable lesion for this study. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 


UCDCC#255 
Protocol Version: 4.0 (07-14-2017)   
 
49 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on 
the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up.  
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  


UCDCC#255 
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50 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of 
the type and site of disease.  Furthermore, as with CT, the modality used at follow-up 
should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used 
and the image acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning techniques, if 
possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 


UCDCC#255 
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51 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have 
been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New 
lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 


UCDCC#255 
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52 
  
Response Criteria 
  
Evaluation of Target Lesions 
Complete Response (CR): 
  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD):  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 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 
 
Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, 
not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
 


UCDCC#255 
Protocol Version: 4.0 (07-14-2017)   
 
53 
For Patients with Measurable Disease (i.e., Target Disease) 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 wks. from 
baseline** 
PD 
Any 
Yes 
or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after discontinuation of treatment. 


UCDCC#255 
Protocol Version: 4.0 (07-14-2017)   
 
54 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.   
Duration of Disease Control 
If an intermittent oxaliplatin strategy is chosen, the duration of disease control will be measured.  
Duration of disease control (DDC) is defined as the addition of the initial PFS and the PFS of the 
reintroduction, except in case of progression at the first evaluation after FOLFOX reintroduction 
[79, 80]. 
 
 

ICF_001.pdf: 
I R B A p pr o v al N u m b er 7 3 6 2 5 3  
U C D C C # 2 5 5  
 
( U p d at e d 5/ 1 4)                                                                                
1  
 
U ni v er sit y of C alif or ni a 
P er mi s si o n t o U s e P er s o n al H e alt h I nf or m ati o n f or R e s e ar c h 
 
St u d y Title:  U C D C C # 2 5 5 – Pil ot St u d y of a [ 1 4 C ] O x ali pl ati n Mi cr o s d o si n g A s s a y t o 
Pr e di ct E x p o s ur e a n d S e n siti vit y t o O x ali pl ati n -B a s e d C h e m ot h er a p y i n A d v a n c e d 
C ol or e ct a l C a n c er 
 
S p o n s or/ F u n di n g A g e n c y:  U C D a vi s C o m pr e h e n si v e C a n c er C e nt er/ U. S. D e p art m e nt 
of E n er g y a n d N ati o n al C a n c er I n stit ut e  
A.  W h at i s t h e p ur p o s e of t hi s f or m ?  
St at e  a n d  f e d er al  pri v a c y  l a w s  pr ot e ct  t h e  u s e  a n d  r el e a s e  of  y o ur  h e alt h 
i nf or m ati o n.  U n d er  t h e s e  l a w s,  t h e  U ni v er sit y  of  C alif or ni a  or  y o ur  h e alt h  c ar e 
pr o vi d er c a n n ot r el e a s e y o ur h e alt h i nf or m ati o n t o t h e r e s e ar c h t e a m u nl e s s y o u gi v e 
y o ur  p er mi s si o n.  T h e  r e s e ar c h  t e a m  i n cl u d e s  t h e  r e s e ar c h er s  a n d  p e o pl e  hir e d  b y 
t h e  U ni v er sit y  or  t h e  s p o n s or  t o  d o  t h e  r e s e ar c h.  If  y o u  d e ci d e  t o  giv e  y o ur 
p er mi s si o n  a n d  t o  p arti ci p at e  i n  t h e  st u d y,  y o u  m u st  si g n  t hi s  f or m  a s  w ell  a s  t h e 
C o n s e nt F or m. T hi s f or m d e s cri b e s t h e diff er e nt w a y s t h at t h e r e s e ar c h er, r e s e ar c h 
t e a m a n d r e s e ar c h s p o n s or m a y u s e y o ur h e alt h i nf or m ati o n f or t h e r e s e ar c h st u d y. 
T h e r e s e ar c h t e a m will u s e a n d pr ot e ct y o ur i nf or m ati o n a s d e s cri b e d i n t h e att a c h e d 
C o n s e nt  F or m .    H o w e v er,  o n c e  y o ur  h e alt h  i nf or m ati o n  i s  r el e a s e d  it  m a y  n ot  b e 
pr ot e ct e d  b y t h e  pri v a c y  l a w s a n d  mi g ht  b e  s h ar e d  wit h  ot h er s.  If  y o u  h a v e 
q u e sti o n s, a s k a  m e m b er of t h e r e s e ar c h t e a m.  
 
B. W h at P er s o n al H e alt h I nf or m ati o n will b e r el e a s e d ?  
 
If  y o u  gi v e  y o ur  p er mi s si o n  a n d  si g n  t hi s  f or m,  y o u  ar e  all o wi n g y o ur h e alt h  c ar e 
pr o vi d er  t o  r el e a s e  t h e  f oll o wi n g  m e di c al  r e c or d s  c o nt ai ni n g  y o ur  P er s o n al  H e alt h 
I nf or mati o n.  Y o ur  P er s o n al  H e alt h  I nf or m ati o n  i n cl u d e s  h e alt h  i nf or m ati o n  i n  y o ur 
m e di c al  r e c or d s  a n d  i nf or m ati o n  t h at  c a n  i d e ntif y  y o u.  F or  e x a m pl e,  P er s o n al  H e alt h 
I nf or m ati o n m a y i n cl u d e y o ur n a m e, a d dr e s s, p h o n e n u m b er or s o ci al s e c urit y n u m b er.  
 
x E ntir e M e di c al R e c or d  
 R a diolo g y R e p orts 
 P at h olo g y R e p orts 
 La b ora t or y R e p orts 
 D e ntal R e c or ds 
 O p e rative R e p orts 
 E m er g e n c y Me dicin e 
C e nt er R e p ort s  
 P r o gre s s N ote s 
 Hist or y & P h ysic al 
E x a m s  
 Dis c h ar g e S u m m a r y 
 C o ns ultatio ns 
 O u t p a tie n t C lin ic  
R e c or d s  
 E K G 
 R a diolo g y i m a g e s  
 P s yc h olo gic al Te sts 
 H e alt h C a re Billin g 
St at e m e nt s  
 Ot h e r: 


IRB Approval Number 736253 
UCDCC#255 
 
(Updated 5/14)                                                                                
2
C. Do I have to give my permission for certain specific uses? 
Yes. The following information will only be released if you give your specific permission 
by putting your initials on the line(s). 
____ I agree to the release of information pertaining to drug and alcohol abuse, 
diagnosis or treatment. 
____ I agree to the release of HIV/AIDS testing information. 
____ I agree to the release of genetic testing information. 
____ I agree to the release of information pertaining to mental health diagnosis or 
treatment as follows: 
_____________________________________________________. 
 
D. How will my Personal Health Information be used? 
 
Your Personal Health Information may be released to these people for the following 
purposes: 
1. To the research team for the research described in the attached Consent Form; 
2. To others at UC who are required by law to review the research; 
3. To others who are required by law to review the quality and safety of the 
research, including: U.S. government agencies, such as the Food and Drug 
Administration and Department of Health and Human Services,  the research 
sponsor or the sponsor’s affiliate organization,  or government agencies in other 
countries. These organizations and their representatives may see your Personal 
Health Information. They may not copy or take it from your medical records 
unless permitted or required by law. 
 
Your PHI used in this study will include all information which is used to determine your 
eligibility and collected from the procedures and tests that are carried out as part of this 
study. This may include, but is not limited to, the following types of medical information 
• Medical information about you including your medical history and present/past 
medications. 
• Results of exams, procedures and tests you have before and during the study. 
• Laboratory test results. 
E. How will my Personal Health Information be used in a research report? 
If you agree to be in this study, the research team may fill out a research report. (This 
is sometimes called “a case report”.) The research report will not include your name, 
address, or telephone or social security number. The research report may include your 
date of birth, initials, dates you received medical care, and a tracking code. The 
research report will also include information the research team collects for the study. 
The research team and the research sponsor may use the research report and share it 
with others in the following ways: 


IRB Approval Number 736253 
UCDCC#255 
 
(Updated 5/14)                                                                                
3
1. To perform more research; 
2. Share it with researchers in the U.S. or other countries; 
3. Place it into research databases; 
4. Use it to improve the design of future studies; 
5. Use it to publish articles or for presentations to other researchers; 
6. Share it with business partners of the sponsor; or 
7. File applications with U.S. or foreign government agencies to get approval for 
new drugs or health care products. 
F. AM I REQUIRED TO SIGN THIS DOCUMENT? 
No, you are not required to sign this document.  You will receive the same clinical care 
if you do not sign this document. However, if you do not sign the document, you will not 
be able to participate in this research study.  
G. Does my permission expire? 
This permission to release your Personal Health Information expires 50 years when the 
research ends and all required study monitoring is over. Research reports can be used 
forever.  You have the right to see and copy any of the research data gathered about 
you, but not until the study is complete.  If the research data contains information that 
may affect your health or safety during your participation, the study staff will notify you 
and your personal care doctor(s) of the results.  If needed, the study staff will send a 
copy of the relevant information to your personal care doctor(s) to help them evaluate 
your true condition.  
H. Can I cancel my permission? 
You may revoke your permission at any time. You can do this in two ways. You can 
write to the researcher or you can ask someone on the research team to give you a 
form to fill out to cancel your permission. If you cancel your permission, you may no 
longer be in the research study. You may want to ask someone on the research team if 
canceling will affect your medical treatment. If you cancel, information that was already 
collected and disclosed about you may continue to be used. Also, if the law requires it, 
the sponsor and government agencies may continue to look at your medical records to 
review the quality or safety of the study. 
I. Signature  
If you agree to the use and release of your Personal Health Information, please sign 
below. You will be given a signed copy of this form. 
___________________________________________  
Subject’s Name (print) 
 
 
 
___________________________________________ __________________ 
Subject’s Signature 
Date 


IRB Approval Number 736253 
UCDCC#255 
 
(Updated 5/14)                                                                                
4
 
Note: if the subject is a minor, an individual signing with an “X”, an adult 
incapable of giving consent, or is unable to read the authorization, fill out and 
attach the “special signatures” page (sections “J” and “K”). 
 
 
SPECIAL SIGNATURES PAGE 
 
J. If the subject is a minor, or an individual signing with an “X”, or an adult 
incapable of giving consent (where IRB approved), the legally authorized 
representative or witness signs here: 
 
___________________________________________ ______________________ 
Legally Authorized Representative’s Name 
or Witness to the “X” (print)  
Relationship to the Subject 
 
 
___________________________________________ ______________________ 
Representative or Witness Signature 
Date 
 
 
K. If the subject is unable to read the authorization, the translator or reader and 
a witness sign here: 
 
I have accurately and completely read this Authorization to _____________________ 
(subject’s name) in ________________ (language), the subject’s primary language. 
The subject has verbally affirmed his/her Authorization to me and to the 
witness. 
 
___________________________________________ 
 
Translator or Reader’s Name (print) 
 
 
 
___________________________________________ 
__________________ 
Translator or Reader’s Signature  
Date 
 
 
___________________________________________ 
 
Witness Name (print)  
 
 
 
_____________________________________________ _____________________ 
Witness Signature 
Date 
 


Study - UCDCC#255      
 Consent  
 Page 1 of 13 
Disease site: Various Gastrointestinal Cancers
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 Dated: 07/14/2017   
UNIVERSITY OF CALIFORNIA, DAVIS 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
STUDY TITLE: UCDCC#255 – Pilot Study of a [14C]Oxaliplatin Microsdosing Assay to Predict Exposure and Sensitivity to 
Oxaliplatin-Based Chemotherapy [Protocol Version 4.0 Dated: 07/14/2017] 
Principal Investigator: Edward Kim, MD, PhD 
Department: 
Internal Medicine Division of Hematology/Oncology 
CALIFORNIA SUBJECT’S BILL OF RIGHTS FOR BIOMEDICAL RESEARCH STUDIES 
The rights below are the rights of every person who is asked to be in a medical research study.  As an 
experimental subject, you have the right to: 
•
Be informed of the nature and purpose of the research study.
•
Be given an explanation of the procedures to be followed, and any drug or device to be used.
•
Be given a description of common or important discomforts and risks reasonably to be expected from the study.
•
Be given an explanation of any benefits you might expect.
•
Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be helpful, and their
risks and benefits compared to this study.
•
Be informed of the types of medical treatment, if any, that are available if complications should arise.
•
Be given an opportunity to ask any questions concerning the study or the procedures involved.
•
Be instructed that consent to participate in the study may be withdrawn at any time, and you may discontinue
participation in the study at any time without it being held against you.
•
Be given a signed and dated copy of this document.
•
Be given the opportunity to decide to consent or not to consent to the study without force, fraud, deceit, duress,
coercion, or undue influence.
INTRODUCTION 
This is a research study.  Research studies only include subjects who choose to participate.  Your study doctor will 
explain the clinical trial to you.  As a study participant you have the right to know about the procedures that will be used in 
this research study so that you can make the decision whether or not to participate.  The information presented here is to 
make you better informed so that you may give or withhold your consent to participate in this research study.  Please take 
your time to make your decision and discuss it with your family, friends, or with your personal physician.  If you have any 
questions, you can ask your study doctor for more explanation.   
You are being asked to take part in this study because you have colon, rectal, pancreatic, gastroesophageal, appendiceal 
cancers or small bowel adenocarcinoma that has not previously been treated with a chemotherapy drug called oxaliplatin 
and your doctor has recommended that you undergo treatment with a chemotherapy regimen that contains oxaliplatin 
along with 5-fluorouracil (5-FU) and leucovorin.  This chemotherapy regimen is commonly referred to as FOLFOX.  We 
hope to learn more about your type of cancer.  You must be 18 years of age or older.  In order to participate in this study, 
it will be necessary to give your written consent.  
WHY IS THIS STUDY BEING DONE? 
Oxaliplatin is approved by the US Food and Drug Administration (FDA) for the treatment of colon, rectal, pancreatic, 
gastroesophageal, appendiceal cancers or small bowel adenocarcinoma.  
The goal of this study is to test the feasibility of using microdose-based diagnostics in combination with oxaliplatin-based 
chemotherapy for personalized cancer treatment. 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 2 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHY IS THIS STUDY BEING DONE? (continued) 
14C, a radioactive form of carbon, exists in nature and in your body at a low level. To evaluate the predictive diagnostic 
test of this study, we will label the oxaliplatin with 14C to trace the drug in your body after it is injected. The dose of total 
radioactive oxaliplatin that you will receive is about 1% of the normal chemotherapy dose—enough to evaluate your 
body’s response to the drug but without any expectation of toxic side effects.  The dose of radiation from 14C is less than 
one chest x-ray that you would have during your cancer work up. This dose of oxaliplatin and radiation should not cause  
 
any adverse reaction in your body.  Based on our previous studies, this amount of 14C-labeled oxaliplatin is sufficient for 
the diagnostic study in patients.  Shortly after the diagnostic data is collected, you will be administered oxaliplatin 
chemotherapy.  Your individual response to the therapy as well as any toxic side effects that you encounter will be 
collected and correlated to the diagnostic test. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
We plan to enroll 6 people to this study at the University California Davis Comprehensive Cancer Center.  
 
BEFORE YOU BEGIN THE STUDY 
 
Before you are able to participate in this study, you must have a diagnosis of colon, rectal, pancreatic, gastroesophageal, 
appendiceal cancers or small bowel adenocarcinoma.  If you choose to take part in this study and sign this informed 
consent form, you will complete “pre-study screening tests” to determine if you meet the study requirements.  These 
exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study.   The pre-
study screening tests are listed below. 
 
Pre-study Screening Tests:   
Within 28 days prior to registration a CT (computerized tomography scan) or MRI (magnetic resonance imaging) of the 
chest/abdomen/pelvis and other areas of known disease or newly suspected disease would be performed. 
 
Description of Tests/Procedures:  
 
 
Physical exam:  You will have a physical examination, similar to those done for regular medical care. 
 
 
Blood drawing (venipuncture):  Blood tests will be done 14 days prior to registration.  These tests will include a 
complete blood count and a chemistry panel. 
 
 
CT scan:  you will have a computed tomography (CT) [computerized axial tomography (CAT)] scan of your chest, 
abdomen and pelvis, done every 8 weeks for 6 months and then every 12 weeks plus or minus 2 weeks thereafter, in 
order to check your response.  A CT scan uses special x-ray equipment to make detailed pictures of body tissues and 
organs.  You will need to lie still on a table with your body inside a large doughnut-shaped machine.  The table will 
move and the machine will make clicking and whirring noises as the pictures are taken.  Each CT scan will take about 
15 minutes to a half hour. 
 
 
MRI:  you may have a Magnetic Resonance Imaging (MRI) exam.  For the MRI exam, you will lie down on a narrow 
bed, which will then be placed in a tunnel that is 6 feet long by 22 inches wide and open at each end.  You will need to 
lie there quietly for about one hour, during which time there will be a loud banging noise.  You may feel warm during 
this procedure.  This would be done if your physician feels an MRI would provide better information regarding your 
disease response. 
 
 
Pregnancy Test (if applicable): Because the chemotherapy drugs and the drug in this study can affect a fetus, if you 
are a woman of childbearing potential, a urine (or blood) test will be done at the initial visit to make sure you are not 
pregnant. 
 
 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 3 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
 
If you decide to participate in this study, you will be asked to do the following:   
 
The following procedures are part of regular care and may be done even if you do not join the study:   
 
You will be seen by the physician for a history and physical exam before each cycle of chemotherapy. You will have blood 
tests before each cycle of chemotherapy. These blood tests include complete blood count and chemistry panel to check 
your liver and kidney function. You will also have X-ray, CT and/or MRI after every two cycles (6 weeks) of chemotherapy 
while you are on the study. 
 
The following procedures are NOT PART OF REGULAR CARE AND WILL ONLY BE DONE IF YOU JOIN THE 
STUDY:  
 
If the screening exams, tests or procedures show that you can continue to be in the study, and you choose to take part, 
then you will have the following tests and procedures done.  
 
There are two parts in this study. Oxaliplatin works by binding to DNA, the genetic material in your cells, forming drug-
DNA damage called adducts.  The first part of this study is to measure 14C-labeled oxaliplatin dose levels after 
administering a microdose of 14C-labeled oxaliplatin to you.  We will also measure the levels of DNA adducts induced by 
administering a microdose with a blood test.  
 
• 
You will have 8 ml (one teaspoon is 5ml) of blood drawn, and receive a microdose of 14C-labeled oxaliplatin 
infused over 2 minutes at the Cancer Center Infusion Center located at the third floor of Cancer Center, 4501 X 
Street, Sacramento, CA 95817.  
 
• 
Four ml of blood samples are collected just before the administration of 14C-labeled oxaliplatin, and at 30 minutes, 
1 hour, 1 hour 45 minutes, 2 hours, 2 hours 15 minutes, 3 hours, 4 hours, and 24 hours after starting the 
[14C]oxaliplatin infusion.  To minimize the venipuncture, a temporary catheter will be placed in your forearm for 
blood draws. 
 
The second part of this study is to receive chemotherapy combined with a microdose of 14C-labeled oxaliplatin.   
 
• 
You will receive a chemotherapy regimen (FOLFOX) that contains oxaliplatin chemotherapy for the treatment of 
your cancer. Oxaliplatin is given through intravenous injection over two hours once every two weeks on the first 
day. This is called one cycle. During the first treatment, a microdose of 14C-labeled oxaliplatin will be administered 
with your treatment dose of oxaliplatin.  The microdose of 14C-labeled oxaliplatin will only be administered with the 
first cycle of treatment. 
 
• 
Four ml of blood samples are collected just before the administration of FOLFOX, and at 30 minutes, 1 hour, 1 
hour 45 minutes, 2 hours, 2 hours 15 minutes, 3 hours, 4 hours, 24 hours and 48 hours post FOLFOX 
administration. To minimize the venipuncture, a temporary catheter will be placed in your forearm for blood draws. 
 
You will continue to be treated with FOLFOX as directed by your doctor.  You will be evaluated before each cycle of 
chemotherapy for any toxicity just like you receive any other chemotherapy. You will be evaluated for tumor response 
after every four cycles (8 weeks) with physician’s visit, CT and/or MRI examination. You will continue to receive oxaliplatin 
chemotherapy if your cancer is responsive to this drug and you do not have a toxic response preventing further treatment 
or until your doctor decides it is time for a break from the oxaliplatin.   
 
 
 
 
 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 4 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? (continued) 
 
Another way to find out what will happen to me during the study is to read the chart/table below.  
PERIOD 
Pre- 
Studya 
Phase 0 
Microdose 
Cycle 
1 
+ 
Microdose 
Ongoing Treatment 
Off Study 
 
 
Day 
1 
 
Day  
2 
 
Day  
1 
 
Day 
2 
 
Day  
3 
Cycle 2, 
Day 1 
Ongoing 
Treatment 
Safety Assessments b   
History & Physical Exam 
X 
 
 
X 
 
 
X 
* 
 
Vital Signs 
X 
X 
 
X 
 
 
X 
* 
 
Performance Status 
X 
 
 
X 
 
 
X 
 
 
Hematology 
X 
X 
 
X 
 
 
X 
* 
 
Serum Chemistries 
X 
X 
 
X 
 
 
X 
* 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Adverse Events 
 
X-------------------------------------------------------
 
 
Efficacy Assessments 
Imaging Studies 
X 
 
 
 
 
 
 
Xc 
X 
Treatments 
[14C]Oxaliplatin Microdose 
 
X 
 
X 
 
 
 
 
 
FOLFOX 
 
 
 
X-------------------------
----X 
X 
* 
 
Biologic Agent, if 
appropriate 
 
 
 
 
 
X 
 
* 
 
Correlative Studies 
Plasma Pharmacokinetics 
 
X 
X 
X 
X 
X 
 
 
 
PBMCs (Peripheral Blood 
Mononuclear Cells)  
Blood Draw 
 
X 
X 
X 
X 
X 
 
 
 
a Pre-study assessments within 14 days before registration, except for imaging studies within 28 days of 
registration 
b All on study safety assessments may be performed +/- 72 hours of the indicated time point 
c Every 8 weeks (+/- 1 week) for 6 months then every 12 weeks (+/- 2 weeks) until progression 
* After Cycle 2, Day 1 and resolution of all microdose-associated toxicities, all safety assessments and 
treatments are at the discretion of the treating investigator according to good medical practice. 
 
Study location: UC Davis is currently coordinating the enrollment of patients for this study at the sites listed below.  We 
anticipate that your treatment will be administered (given) at the site of your enrollment. 
 
UC Davis Comprehensive Cancer Center 
4501 X Street 
Sacramento, CA 95817 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 5 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
HOW LONG WILL I BE IN THE STUDY? 
 
You will be asked to participate for as long as you are not having any unmanageable side effects. After you are finished 
with the [14C] oxaliplatin study procedures, your medical chart will be available to the researchers in order to monitor your 
progress during chemotherapy and follow up care. There are no extra follow-up visits or tests related to this study after the 
off study visit. 
 
CAN I STOP BEING IN THE STUDY? 
 
Yes.  You can decide to stop at any time.  Tell your study doctor if you are thinking about stopping or decide to stop.  Your 
doctor will tell you how to stop safely.  It is important to tell the study doctor if you are thinking about stopping so any risks 
from oxaliplatin can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping is 
to discuss what follow-up care and testing could be most helpful for you. If you are off study, you will need to have an off 
study visit, which will involve blood draws, bone scans, and CT if indicated.  
 
Your study doctor may stop you from taking part in this study at any time if he or she believes it is in your best interest; if 
you do not follow the study rules; or if the study is stopped. 
 
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? 
 
Risks and side effects related to 5-fluorouracil (5-FU): 
 
Likely risks related to 5-fluorouracil (events occurring greater than 20% of the time): 
• 
Darkening of skin and nail beds; dry, flaky skin 
• 
Decreased white blood cells, the infection-fighting cells, which could put you at risk for infection 
• 
Decreased number of platelets, the blood-clotting cells, which could put you at increased risk of bleeding 
• 
Nausea 
• 
Vomiting 
• 
Sores in the mouth or on the lips 
• 
Thinning hair 
• 
Diarrhea 
• 
Brittle nail 
• 
Increased sensitivity to the sun 
 
Less likely risks related to 5-fluorouracil (events occurring less than or equal to 20% of the time): 
• 
Darkening and stiffening of the vein used for giving the drug 
• 
Decreased appetite 
• 
Headache 
• 
Weakness 
• 
Muscle aches 
 
Rare but serious risks related to 5-fluorouracil (events occurring less than or equal to 2-3 % of the time): 
• 
Difficulty walking 
• 
Irritation of the eyes 
• 
Increased tearing of the eyes 
• 
Blurred vision 
 
While you are being treated with 5-fluorouracil and after you stop treatment, do not have any immunizations (vaccinations) 
without first asking your doctor for approval. Try to avoid contact with people who have recently received the oral polio 
vaccine and check with your doctor about this. 
 
Risks and side effects related to leucovorin: 
 
Side effects that you may experience with this drug are uncommon. These, however, include an allergic reaction, varying 
from an itchy rash to breathing difficulties. Measures are available to help you if these should occur. 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 6 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
 
Leucovorin may interfere with the effects of anti-seizure medications such as phenobarbital, phenytoin, and primidone. 
When leucovorin is given together with the drug called 5-fluorouracil, it may increase its side effects. 
 
Risks and side effects related to oxaliplatin chemotherapy: 
Likely (events occurring greater than 20% of the time): 
• 
Lack of enough red blood cells (anemia which may make you short of breath, weak, fatigued, or tired)  
• 
Diarrhea, which could lead to dehydration  
• 
Nausea or vomiting  
• 
Fatigue or tiredness  
• 
Abnormal liver function as seen on a blood test  
• 
Decreased number of a type of blood cell (platelet) that helps to clot blood (may result in easy bruising or 
bleeding)  
• 
Damage to nerves causing numbness, tingling, burning  
• 
Decreased number of a type of white blood cell (lymphocyte) that can lead to infection  
• 
Decreased number of a type of white blood cell (neutrophil/granulocyte) that can lead to infection  
• 
Temporary hair thinning or loss  
• 
Sores in the mouth and/or throat  
• 
A sensation of pain or tingling in areas of the body that are exposed to cold air or cold liquid, such as your hands 
if placed in the refrigerator or your throat if exposed to a cold wind or drinking cold liquids (see the Additional 
Information section below).  
• 
Dizziness  
• 
Changes in fingernails  
• 
Loss of appetite  
• 
Taste changes  
• 
Headache  
 
Less likely (events occurring less than or equal to 20% of the time): 
• 
Abnormal blood clotting and/or bleeding  
• 
Fever associated with dangerously low levels of a type of white blood cell (neutrophils)  
• 
Destruction of red blood cells  
• 
Abnormal heart rhythm  
• 
Hearing loss  
• 
Inflammation of the ear  
• 
Swelling and redness of the eye and eyelids.  
• 
Dry or watery eyes  
• 
Temporary vision problems caused by the cold  
• 
Drooping eyelid  
• 
Swelling around the nerve responsible for sight  
• 
Belly pain  
• 
Fluid collection in the abdomen  
• 
Constipation  
• 
Dry mouth  
• 
Heartburn  
• 
Difficulty swallowing  
• 
Excess passing of gas  
• 
Irritation of the stomach  
• 
Bleeding in some organ(s) of the digestive tract, for example, blood in your stool  
• 
Death of tissue somewhere in the digestive tract  
• 
Sore (ulcer) in the digestive tract, including esophagus or intestines  
• 
Blockage of the intestines with severe constipation  
• 
Inflammation of the pancreas that can cause belly pain and may be serious  
• 
Chills  
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 7 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Less likely (events occurring less than or equal to 20% of the time): Continued 
 
• 
Swelling of the face, arms or legs  
• 
Fever  
• 
Difficulty walking  
• 
A condition in which both the liver and kidneys fail  
• 
Irritation at the site of the IV  
• 
Chest pain which is not heart-related  
• 
Liver failure  
• 
Increase in size of the liver  
• 
Blockage of the veins of the liver leading to liver damage  
• 
Allergic reaction (rash, redness, itching, watery or swollen eyes, throat swelling, shortness of breath)  
• 
Infection  
• 
Slow blood clotting as seen on a blood test: PTT, INR  
• 
Abnormal kidney function as seen on a blood test  
• 
Abnormal liver function as seen on a blood test  
• 
Abnormal test of bone health: alkaline phosphatase  
• 
Weight gain or weight loss  
• 
Dehydration  
• 
Increased or decreased blood sugar level  
• 
Decreased levels of a protein called albumin  
• 
Abnormal blood chemistries that could lead to abnormal heart, kidney, or nerve function: blood acid, uric acid, 
calcium, potassium, magnesium, sodium, phosphate  
• 
Pain including joint, back, bone, and muscle  
• 
Difficulty or limitation in ability to open mouth  
• 
Sleepiness  
 
Less likely (events occurring less than or equal to 20% of the time) 
• 
Speech problems  
• 
Abnormal or involuntary movements  
• 
Bleeding in the brain  
• 
Stroke or mini-stroke (TIA)  
• 
A malfunction of the nerves within the head and neck  
• 
Weakness or paralysis caused by damage to nerves  
• 
Convulsion or seizure  
• 
Anxiety  
• 
Confusion  
• 
Depression  
• 
Difficulty sleeping or falling asleep  
• 
Blood in the urine  
• 
Bleeding in the kidney  
• 
Need to urinate often  
• 
Difficulty emptying the bladder  
• 
Bleeding in male or female reproductive organs  
• 
Stuffy or runny nose, sneezing  
• 
Bleeding in the respiratory tract  
• 
Throat tightness, shortness of breath, or a choking sensation (see the Additional Information section below)  
• 
Cough, wheezing  
• 
Hiccups  
• 
Inflammation of the lungs  
• 
Scarring of the lungs that can cause shortness of breath and interfere with breathing  
• 
Problem of the sinuses  
• 
Voice change  
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 8 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
Less likely (events occurring less than or equal to 20% of the time): (Continued) 
 
• 
Dry skin  
• 
Excess sweating  
• 
Itching  
• 
Skin rash or hives  
• 
Sudden reddening of the face and/or neck  
• 
Hot flashes  
• 
High or low blood pressure  
• 
Inflammation of a vein  
• 
Formation of a blood clot that could break loose and be carried by the blood stream to block another blood vessel  
• 
Swelling and redness of the skin on the palms of the hands and soles of the feet that could be serious  
• 
Kidney damage that could be severe (see the Additional Information section below)  
 
Rare but serious: (events occurring less than or equal to 2-3 % of the time):  
• 
Formation of blood clots in small blood vessels around the body that leads to a low platelet (a type of blood cell 
that helps to clot blood) count  
• 
Gas in the intestinal (bowel) wall  
• 
Inflammation of the gallbladder possibly associated with gall stones  
• 
Sudden or traumatic injury to the kidney  
• 
Severe potentially life-threatening damage to the lungs which can lead to difficulty breathing  
• 
Clotted catheter or catheter infection  
• 
Severe diarrhea that may be life threatening  
• 
Heart problems (chest pain, heart attack)  
• 
Accumulation of fluid around the heart  
 
Additional information about the risks of oxaliplatin  
Exposure to cold (oxaliplatin): When receiving oxaliplatin, the nerves that affect your throat may be affected and cause a 
strange sensation when swallowing cold liquids. You should avoid cold beverages while you are participating in this study. 
You may also notice a tingling and numbness or pain in your hands and feet that worsen on exposure to cold. Extra layers 
of clothing (gloves, mittens and warm socks) may help these symptoms be less severe. If you should develop throat 
tightness, shortness of breath, or a choking sensation, contact your doctor immediately. In the patients treated with this 
drug, there have been 11 patients (of more than 50,000 who have be treated with oxaliplatin) who have had lung 
problems such as cough, shortness of breath, or trouble breathing. This caused scar tissue in the lungs and these events 
can be life threatening.  
 
Inflammation of the nerves can become worse during the time you are receiving treatment, and the risk of developing it 
increases with the amount of oxaliplatin you receive. This inflammation usually goes away.   
 
In some cases, oxaliplatin can cause a severe infection. This infection is serious and can be life threatening. Contact your 
physician immediately if you are experiencing severe diarrhea (more than 7 or 8 times per day), fever, as well as 
numbness or tingling in your hands, feet or throat, or weakness.  
 
A few patients treated with oxaliplatin have developed kidney damage. The damage to the kidneys may lead to the need 
for kidney dialysis usually on a temporary basis. You may also develop a condition associated with the dysfunction of your 
kidneys called Hemolytic Uremic Syndrome. This syndrome can be serious and may lead to seizures, problems with the 
central nervous system, or coma.  
 
Platinum drugs like oxaliplatin have been known to cause leukemia in a small number of patients. It is not known whether 
risk of future development of leukemia is a side effect of oxaliplatin. One case of leukemia and one case of 
myelodysplastic syndrome, a condition which could lead to leukemia, have been seen following oxaliplatin chemotherapy, 
although it is not certain that oxaliplatin caused these blood disorders. 
 
Oxaliplatin has caused severe immune reactions in 2-3% of colon cancer patients, which can be fatal. These reactions are 
usually managed with other drug treatments such as epinephrine, corticosteroid and antihistamine therapy. 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 9 of 13 
Disease site: Various Gastrointestinal Cancers 
 
UCDCC#255_Consent_11.02.17_clean.doc 
Protocol Version 4.0 dated 07/14/2017  
 
 
                                                  
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? (continued) 
General Risks: 
 
• 
Venipuncture/Intravenous (IV) Needle Insertion:  Routine laboratory tests and the research blood draws, which 
may result in bruising, infection and minor pain or discomfort comparable to a needle prick. 
• 
Radiation (x-ray) risks: X-rays will be performed even if you do not participate in this trial. They are a part of the 
routine studies for the treatment of your cancer. This study involves a low radiation exposure from 14C-labeled 
oxaliplatin that is about the same as the radiation exposure from one chest x-ray. The amount of radiation 
exposure is below the level that is considered to be a significant risk of harmful effects. 
 
• 
CT scan risks:  CT scans will be performed even if you do not participate in this trial. They are not part of this 
study. They are part of the routine studies for the treatment of your cancer. CT scans involve radiation exposures 
that are higher than other diagnostic tests using ionizing radiation. The exposure to radiation from this study might 
result in a slight increase in cancer risk in normal healthy individuals. However, since you already have cancer, a 
risk estimate cannot be accurately determined. 
 
In addition, if contrast material (iodine dye) is used, there is a slight risk of developing an allergic reaction, from 
mild (itching, rash) to severe (difficulty breathing, shock, or rarely, death).  The contrast material may also cause 
kidney problems, especially if you are dehydrated or have poor kidney function.  The study doctors will ask you 
about any allergies or related conditions before the procedure.  If you have any of these problems, you may not 
be allowed to have a CT scan. 
 
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered by feelings of 
claustrophobia when placed inside the CT scanner, or by lying in one position for a long time.  If contrast material 
is used, you may feel discomfort when it is injected.  You may feel warm and flushed and get a metallic taste in 
your mouth. Rarely, the contrast material may cause nausea, vomiting or a headache.   
 
• 
Reproductive Risks:  You should not become pregnant or father a baby while on this study because the 
chemotherapy drugs you will receive and the drugs in this study can affect an unborn baby.  Women should not 
breastfeed a baby while on this study.  It is important to understand that you need to use birth control while on this 
study. Women of child-bearing potential must use hormonal or barrier contraception or abstinence and men must 
agree to barrier method or abstinence both must be used prior to study entry and 30 days after study 
participation.    Even though 14C-labeled oxaliplatin used in this study is very small, the subsequent chemotherapy 
drugs you receive may make you unable to have children in the future. 
 
• 
Unknown Risks: There is a very small chance the microdose in this study may cause the chemotherapy treatment 
that you receive after being on this study to be less effective.   
 
• 
MRI risks:  Because the MRI machine acts like a large magnet, it could move iron-containing objects in the MRI 
room during the examination. Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room. The risks to a fetus from MRI are 
unknown; pregnant women cannot participate in this study. 
 
• 
Unknown Risks: The experimental treatments may have side effects that no one knows about yet. The 
researchers will tell you of new information that might make you change your mind about participating in the 
study. 
 
For more information about risks and side effects, ask your study doctor. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
You may not benefit from taking part in this research.  The information we get from this study may help us to learn more 
about this study treatment, and this may help future cancer patients. 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
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WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
Your alternative is not to take part in this study.  If you choose not to take part in this study, your future care will not be 
affected.  Your other choices may include: 
 
 
Getting treatment or care for your cancer without being in a study 
 
Participating in a different study, if available 
 
Getting no treatment 
 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems, and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries to 
improve how you feel.  Comfort care tries to keep you as active and comfortable as possible. 
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
 
We will do our best to make sure that your personal information will be kept private.  However, we cannot guarantee total 
privacy. Your personal information may be given out if required by law.  
 
If information from the study is published or presented at scientific meetings, your name and other personal information 
will not be used.     
 
Organizations that may look at and/or copy your research records for research, quality assurance, and data analysis 
include: 
 The investigators involved in the conduct of this study and their designees 
 The financial sponsor of this study Accelerated Medical Diagnostics Incorporated 
 The National Cancer Institute (NCI) 
 The US Food and Drug Administration (FDA) 
 The UC Davis Institutional Review Board (IRB) 
 Lawrence Livermore National Laboratory 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law.   This Web site 
will not include information that can identify you.   At most, the Web site will include a summary of study results.   You can 
search this Web site at any time.  
If we access protected health information (e.g., your medical record), you will be asked to sign a separate form to give 
your permission. Your medical records may become part of the research record.  If that happens, your research records 
may be looked at by the sponsor of this study and government agencies or other groups associated with the study. 
 
Federal law provides additional protections of your medical records and related health information. These are described in 
the UC Davis Health System Notice of Privacy Practices (http://www.ucdmc.ucdavis.edu/legal/privacy/) and in an attached 
document. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
It is important that you promptly tell the person in charge of this research if you believe that you have been injured 
because of taking part in this study. If you are injured as a result of being in this study, the University of California will 
provide necessary medical treatment. Depending on the circumstances, the costs of the treatment may be covered by the 
University or the study sponsor or may be billed to your insurance company just like other medical costs. The University 
and the study sponsor do not normally provide any other form of compensation for injury. For more information about 
compensation, you may call the IRB Administration at (916) 703-9151 or email at hs-IRBAdmin@ucdavis.edu 
 
If the sponsor pays any of your medical expenses, we may be required to give the sponsor your name, date of birth, and 
Medicare ID or social security number. 
 
 
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


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WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
Accelerated Medical Diagnostics, Inc. will provide [14C]Oxaliplatin free of charge for this study.  Every effort will be made 
to ensure adequate supplies of [14C]Oxaliplatin for all participants.   
 
There will be no charge to you or your insurance company for processing the research blood draws or research studies on 
your tumor biopsy tissue and blood tests. They will be paid for by the study.  However, if the specimens are obtained 
during a standard diagnostic procedure, that procedure will be charged to you or you insurance company in the usual 
way. 
 
5-FU, leucovorin, and oxaliplatin (FOLFOX) are commercially available and will be billed to you and/or your insurance 
company. 
 
You or your insurance carrier will be responsible for the associated costs of administering FOLFOX including infusion 
room charges, costs of the drugs, all routine laboratory tests, x-rays, scans, clinic visits or hospital stays. However, you or 
your insurance carrier will not be asked to bear the cost of any tests or procedures done solely for research purposes.  
 
Whenever possible, pre-authorization will be obtained.  If the costs are not covered, these costs will be discussed prior to 
proceeding with the study. 
 
For more information about possible costs, please contact the research team. The research team can follow UC Davis 
Uninsured Non-Emergency Estimate Policy (Policy ID 1883) to work with their department and Decision Support Services 
to get you a cost estimate. 
 
WILL I BE COMPENSATED FOR BEING IN THIS STUDY? 
 
You will not be compensated for your participation in this study. 
 
Samples taken during this study may be used for research and development purposes not related to your treatment or 
condition.  You will not have any property rights or ownership interest in products or data which may be derived from 
your samples. 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.  No matter what decision you make, there will be 
no penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your medical care.  
You can still get your medical care from our institution.   
 
We will tell you about new information or changes in the study that may affect your health or willingness to continue in 
the study.   
 
DOES THE RESEARCHER HAVE A FINANCIAL INTEREST IN THIS RESEARCH STUDY?  
 
The Principal Investigator does not have any personal or financial interest in this study.  Edward Kim, MD, MS from the 
UC Davis Cancer Center is conducting the study. Some of the specimens obtained from you during this will study will be 
analyzed at Lawrence Livermore National Laboratory (LLNL), Livermore, CA. The University of California at Davis 
Cancer Center, the United States Department of Energy, and National Cancer Institute (NCI) are funding part of this 
clinical study. The Department of Energy is giving money to LLNL so that the study doctors from UC Davis and LLNL 
can conduct the study. NCI is giving money to a company named Accelerated Medical Diagnostics, Inc, to support this 
trial. Drs. Pan and Henderson, co-investigators have ownership interest in Accelerated Medical Diagnostics, Inc. 
 
Bio-specimens (such as blood, tissue, or saliva) collected from you for this study and/or information obtained from your 
bio-specimens may be used in this research or other research, and shared with other organizations. You will not share 
in any commercial value or profit derived from the use of your bio-specimens and/or information obtained from them. 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


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WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the research team at 
. If you are unable to the reach the Principal Investigator of this study, please contact the clinical research 
coordinator (CRC) responsible for your care. The CRC's contact information will be provided to you. The CRC will assist 
you in contacting another investigator for this study.  For non-emergency issues you can call the UCDMC Hospital 
Operator (916-734-2011), tell the Operator you are participating in a research study and you wish to talk to the medical 
oncologist on call.  In the case of an emergency, dial 911 from any phone. 
 
 
UC Davis Contact information (including the 24-hour number) is summarized below:  
 
Edward Kim, M.D. 
 
  
 
 
 
 
This research has been reviewed and approved by an Institutional Review Board (“IRB”). Information to help you 
understand research is on-line at http://www.research.ucdavis.edu/policiescompliance/irb-admin/.You may talk to an IRB 
staff member at 
 
for any of the following: 
 
• 
Your questions, concerns, or complaints are not being answered by the research team. 
• 
You cannot reach the research team. 
• 
You want to talk to someone besides the research team. 
• 
You have questions about your rights as a research subject. 
• 
You want to get information or provide input about this research. 
 
WHERE CAN I GET MORE INFORMATION? 
  
You may call the National Cancer Institute's Cancer Information Service at:   
  
1-800-4-CANCER (1-800-422-6237)  
  
You may also visit the NCI Web site at http://cancer.gov/   
  
•   For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/   
•   For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/   
 
VOLUNTARY CONSENT: 
 
My signature below will indicate that I have decided to participate in this study as a research subject.  I have 
read and understand the information above.  I understand that I will be given a signed and dated copy of this 
consent form and the Bill of Rights.   
 
 
 
 
 
 
 
 
 
 
Signature of Subject  
Printed Name of Subject 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
Printed Name of Person Obtaining Consent 
Date 
 
   
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017


Study: UCDCC #255 Drug(s)                                                            Consent                                                                                                    Page 13 of 13 
Disease site: Various Gastrointestinal Cancers 
 
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~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 
 
 
SIGN BELOW ONLY IF A WITNESS WILL OBSERVE THE CONSENT PROCESS (for use with IRB “Short Form”) 
 
 
 
 
 
 
 
 
 
Signature of Witness to Consent Process  
Printed Name of Witness 
Date  
 
 
 
 
 
APPROVED by the Institutional Review Board 
at the University of California, Davis 
Protocol 
Approved 
 
 
736253
November 15, 2017