Conditions: Unresectable Intrahepatic Cholangiocarcinoma
Keywords: LC Bead Irinotecan ONCOZENE BEAD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if the combination of trans-arterial chemoembolization (LC or ONCOZENE BEAD) plus infusional chemotherapy is safe and more effective than just receiving the infusional chemotherapy alone.

Detailed description:

Arms:
arm 1: Transarterial Chemoembolization (LC or ONCOZENE Bead) with Gem-Cis or Gem-Carbo arm 2: Gem-Cis or Gem-Carbo alone

Interventions: intervention 1: LC or ONCOZENE Bead with Gem-Cis or Gem-Carbo intervention 2: Gem-Cis or Gem-Carbo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
Title of Study:  
Drug-Eluting Bead, Irinotecan Therapy of Unresectable Intrahepatic 
Cholangiocarcinoma (DELTIC) with Concomitant Systemic Gemcitabine 
and Cisplatin or Carboplatin 
 
 
Date Issued: 3/30/2017 
 
NCT01648023 
 
 
 
 
 


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Investigational Plan & Clinical Study Protocol 
 
 
 
 
 
 
 
 
 
Drug-ELuting Bead, Irinotecan Therapy of Unresectable Intrahepatic 
Cholangiocarcinoma (DELTIC) with Concomitant Systemic Gemcitabine and 
Cisplatin or Carboplatin 
 
 
 
PROTOCOL #: UL 2011.1 
 
Date Issued: March 30, 2017 
 
 
 
 
 
 
 
 
 
Sponsor/Investigator: 
University of Louisville 
Department of Surgery, Division of Surgical Oncology 
Robert C.G. Martin II, MD, PhD 
315 East Broadway, Suite 311 
Louisville, KY 40202 
Telephone: 502-629-3355 
Fax: 502-629-3030 
E-mail: robert.martin@louisville.edu 


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1 Protocol Synopsis 
1.1 
Title 
Drug-Eluting Bead, Irinotecan (DEBIRI) Therapy of Unresectable intrahepatic 
cholangiocarcinoma (ICC) with Concomitant Systemic Gemcitabine and Cisplatin 
(Gem-Cis) or Gemcitabine and Carboplatin (Gem-Carbo) 
Comparative,  prospective,  open-labeled,  randomized  phase  II  study of  Cisplatin or 
Carboplatin with Gemcitabine in combination with  Irinotecan-loaded  beads (LC or 
ONCOZENE) versus  Cisplatin or Carboplatin with Gemcitabine  alone  in  the  
treatment  of  patients  with  unresectable intra-hepatic cholangiocarcinoma. 
1.2 
Objectives 
The primary objective of this study is to confirm the efficacy of Irinotecan-loaded 
beads (LC or ONCOZENE), in combination with Gem-Cis or Gem-Carbo  intravenous 
chemotherapy  versus Gem-Cis or Gem-Carbo   intravenous   chemotherapy   alone   
in   the   treatment   of   unresectable intra-hepatic cholangiocarcinoma. 
Open label, prospective, randomized phase II study. 
1.3 
Study 
Sponsor 
Robert C.G. Martin, M.D., PhD  
University of Louisville 
1.4 
Primary 
Investigator 
Charles R. Scoggins M.D., MBA 
 
1.5 
Co- 
investigators 
Lawrence Kelly, M.D., Kelly M. McMasters, M.D., Ph.D., Prejesh Philips, M.D., 
Rebecca Redman, M.D., Vivek Sharma, M.D., Cliff Tatum, M.D.  
1.6 
Study Device 
Biocompatibles’ LC beads loaded with Irinotecan (70-150 µm or 100–300µm) or 
Celonova’s ONCOZENE beads (40 µm or 75 µm) loaded with Irinotecan. Maximum 
total dose will be 100mg Irinotecan per procedure in combination with 
Gem-Cis or Gem-Carbo alternating on a 3 week schedule 
1.7 
Primary 
Endpoint 
Primary endpoint will be tumor response according to modified RECIST Criteria 
1.8 
Secondary 
Endpoint 
 
Local Tumor Response (extent of necrosis in the treated lesions) 
 
Progression Free Survival 
 
Hepatic Progression Free Survival 
 
Change in Tumor Markers 
 
Overall Survival (telephone follow-up) 
 
Patient Tolerance 
1.9 
Study Design 
Prospective, open-label, randomized phase II study to compare subjects treated with 
LC beads loaded with Irinotecan or ONCOZENE beads loaded with Irinotecan in 
combination with Gem-Cis or Gem-Carbo chemotherapy to subjects treated 
exclusively with Gem-Cis or Gem-Carbo.  chemotherapy. 
1.10   Number of 
Subjects 
54 subjects will be enrolled and randomized 1 to 1 (27 in each arm). 


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1.11 Eligibility 
Criteria 
Inclusion: 
 
 
• 
Subjects over 18 years of age, of any race or sex, who have histological 
evidence of intrahepatic cholangiocarcinoma, who have been deemed 
unresectable by an experienced hepatic surgeon, and who are able to give 
informed consent, will be eligible 
 
• 
Subjects with at least one measurable liver tumor, with size > 1cm 
(modified RECIST criteria) 
 
• 
Subjects with liver-dominant disease defined as ≥80% of the subject’s total 
amount of malignant disease (tumor burden) that is confined to the liver 
 
• 
Hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 75 x109/L, INR ≤1.3 
(subjects on therapeutic anticoagulants are not eligible if they cannot stop 
their anti-coagulation prior to DELTIC TACE and meet INR criteria) 
 
• 
Adequate liver function as measured by: Total bilirubin ≤ 2.0 mg/dl, AST 
and ALT ≤ 5 ULN, albumin ≥ 2.5 g/dl 
 
• 
Adequate renal function as measured by: Creatinine ≤ 2.0 mg/dl, > 50 
ml/min calculated by the C-G equation 
 
• 
Non-pregnant women of child bearing potential and fertile men are required 
to use effective contraception (negative βHCG for women of child-bearing 
age) 
 
• 
Signed, written informed consent 
 
• 
ECOG status ≤ 2 
 
• 
Liver tumor volume is less than 70% of entire volume of liver. (Less than 
70% tumor replacement) 
 
Exclusion: 
 
• Subject eligible for curative treatment (i.e. resection or tumor ablation) 
 
• 
Active bacterial, viral or fungal infection within 72 hours of study entry 
 
• 
Women who are pregnant or breast feeding 
 
• 
ECOG Performance Status score of ≥3 
 
• 
Life expectancy of < 3 months 
 
• 
PTT > 2.5 ULN and Hgb < 8.0 mg/dl 
 
• 
Patients with a history of Gilberts Syndrome 
 
• 
Patients with a history of UGT1A1 deficiency 
 
• 
Allergy to contrast media that cannot be managed with standard care (e.g. 
steroids), making magnetic resonance imaging (MRI) or computed 
tomography (CT) contraindicated 
 
• 
Presence of another malignancy with the exception of cervical carcinoma in 
situ and stage I basal or squamous cell carcinoma of the skin within 5 years 
of study entry. 


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• Any contraindication for hepatic embolization procedures: 
 
- 
Large shunt as determined by the investigator (pretesting with TcMMA 
not required) 
 
- 
Severe atheromatosis vascular disease that precludes arterial 
cannulization 
 
- 
Hepatofugal blood flow 
 
- 
Main portal vein occlusion (e.g. thrombus or tumor) 
 
• 
Other significant medical or surgical condition, or any medication or 
treatment, that would place the subject at undue risk and that would preclude 
the safe use of chemoembolization or would interfere with study 
participation 
 
• 
Subjects with prior contraindications for the use of Irinotecan, gemcitabine, 
Cisplatin or Carboplatin 
 
• 
Subjects who have received prior systemic therapy with either Irinotecan, 
Gemcitabine, Cisplatin or Carboplatin  
 
• Subjects taking medications that may counteract the study medications. 
These medications include CYP3A4 inducers, such as Rifabutin and St. 
John’s Wort, and CYP3A4 inhibitors such as Ketoconazole. 


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1.12 Chemo- 
embolization 
Procedure 
Using a unilateral femoral (or brachial, if femoral artery is not available) approach, 
selective catheterization of the hepatic artery will be performed. Vascular access is 
obtained via the common femoral artery and a guidewire advanced under 
fluoroscopic guidance. A microcatheter is then inserted over the guidewire. The 
superior mesenteric artery is selected and an angiogram performed to identify any 
aberrant arterial anatomy and verify antegrade portal vein flow (on all embolization 
visits after the first, occlusion of vessels embolized on the previous visit should be 
recorded in the CRF). The celiac axis is then selected and an angiogram completed. 
The catheter and guidewire are used to select the proper hepatic artery and a limited 
angiogram performed to identify the branches of the hepatic artery. The right or left 
hepatic artery is selected distal to the cystic artery (if visualized), depending on the 
location of the lesions to be treated. 
 
Once the vascular supply of the tumor is identified, lobar to selective 
chemoembolization of the supplying artery is performed. At the discretion of the 
interventional radiologist, extrahepatic vessels may be prophylactically embolized in 
order to mitigate risk of non-target deposition of LC beads loaded with Irinotecan 
or ONCOZENE beads loaded with Irinotecan. Subjects with unifocal tumors will be 
treated with super selective chemoembolization. At the discretion of the 
investigator, a microcatheter may be used to select a second or third-order branch 
of the right or left hepatic artery in close proximity to the tumor. For multifocal 
disease or tumor spanning both lobes, embolization of each lobe will be performed 
separately on different treatment days. 
 
Once the catheter is in place within the artery feeding the tumor, the LC beads 
or ONCOZENE beads loaded with Irinotecan will be delivered into the artery. The 
objective of the embolization procedure will be to deliver up to 2 mL (1 vial, 100 mg 
Irinotecan) of the 70-150 µm or 100-300 µm L C  beads. If ONCOZENE beads (40 
µm or 75 µm) loaded with Irinotecan are used, then up to 2ml (1 vial, 100mg 
Irinotecan) of the 40 µm or 75 µm beads will be used. 
 
Radiological non-ionic contrast (preferably Omnipaque) will be used to guide the 
injection of beads. The beads will be mixed with contrast (according to the 
instructions for use) immediately prior to the procedure and injected slowly in 1ml 
aliquots using a “sandwich technique” (i.e. beads then contrast) in order to identify 
and minimize reflux. Catheter selection will be by operator preference (e.g. the 
choice of a microcatheter, in case of tortuous, narrow or spastic vessels).   
 
If vasospasm occurs, vasodilators may be given at the investigator’s discretion. If 
the vasospasm does not resolve, the procedure should be aborted and the subject 
rescheduled. 
 
The catheter will then be removed and hemostasis achieved by manual compression 
or closure device. Each subject will observed for vital signs, femoral access site, pain 
management and fluid hydration per each institution’s standard of care. 
 
The amount of contrast agent delivered to the subject during the procedure and dose 
of irradiation will be recorded as well as the time exposed to fluoroscopic imaging. 
The vessels embolized will be noted and the amount of embolic agent used will be 
recorded. All medications used during the procedure will be recorded, including 
pain management regimen. 


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1.13  Study 
Procedures: Baseline 
Consented   subjects   will   have   the   following   screening/baseline   assessments 
performed prior to the first treatment. 
Within approximately four weeks of the first treatment: 
• 
Detailed medical history including previous cancer history and cancer 
treatment, any medications taken within 30 days prior to study treatment, 
and any additional cancer-related medications taken one year prior to study 
start will also be recorded 
• 
Physical examination including weight, height and vital signs 
• 
Laboratory tests (w/ baseline): CBC, CMP, tumor marker (CA19-9) and 
coagulation (PT, PTT, INR) 
• 
Demographics 
• 
Serum pregnancy test (for women of child bearing potential) 
• 
Documentation of disease status (via a triple phase, thin cut (< 2.5 mm) 
contrasted CT or dynamic MRI of the abdomen and pelvis)  
All sites of disease should be identified by MRI or CT of abdomen/pelvis as well as 
contrasted CT chest and recorded at baseline. At least one measurable hepatic lesion 
must be identified as a target lesion and measured. This scan must be performed 
within approximately 4 weeks prior to first treatment. 
1.14   Study 
Procedures during  
Treatment Period: 
Chemoembolization 
Visits 
Test Group 
Subjects in the “Test Group” will receive chemoembolization(s) with Irinotecan- 
loaded LC beads or ONCOZENE beads in combination with intravenous 
chemotherapy. This group will receive chemoembolization(s) throughout the 
treatment period. 
The following data will be collected from subjects in the “Test Group” before and 
after each chemoembolization procedure: 
• 
Vital signs 
• 
Laboratory Tests: CBC, CMP and magnesium (coagulation as clinically 
indicated) 
• 
Adverse Event Monitoring and Concomitant Medication monitoring 
Control Group 
Subjects in the “Control Group” will receive intravenous chemotherapy only and 
will not receive any chemoembolization procedures for the duration of the study. 
1.15   Study 
Procedures during  
Treatment Period: 
Chemotherapy Visits 
Test Group and Control Group 
Subjects  in  both  the  “Test  Group”  and  in  the  “Control  Group”  will  have  the 
following data collected prior to each systemic chemotherapy infusion: 
• 
Physical Exam or Nursing Assessment 
• 
Vital signs 
• 
Laboratory Tests: CBC, CMP and magnesium (coagulation as clinically 
indicated) 
• 
Adverse Event Monitoring and Concomitant Medication monitoring 
After every 3 chemotherapy cycles, subjects will have their first follow-up CT 
scan and office visit to assess tumor response to treatment. 


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1.16   Study 
Procedures: 
Follow-up Visits 
Test Group and Control Group 
Subjects in both the “Test Group” and in the “Control Group” will remain on study 
until either progression of disease or until discontinuation of study treatments. 
Subjects will then enter into the Follow-Up period, which lasts for approximately 1 
year following their last study treatment. 
During the Follow-Up period, subjects should be assessed and radiologically 
evaluated every 3 – 4 months, as per standard procedures. The following data will 
be collected during these standard, routine follow-up office visits: 
• 
Physical Examination 
• 
Vital signs 
• 
Laboratory Tests: CBC,  CMP and tumor markers (CA19-9) 
• 
Tumor Marker Assessment (approximately every three months) 
CT/MRI of abdomen/pelvis (via a triple phase, thin cut (< 2.5 mm) 
contrasted CT or dynamic MRI of the abdomen and pelvis) for tumor 
response.  
• Adverse events and concomitant medications will be collected on each 
subject for up to 30 days after their last active study treatment. 
1.17   Evaluation 
Procedures 
• 
The primary endpoint will be tumor response rate measured from first 
treatment until progressive disease is reported (as defined by the modified 
RECIST criteria) 
• 
Tumor response will be defined as the best overall response according to 
modified RECIST criteria over all follow up visits from commencement of 
the first treatment 
• 
Local tumor response will be defined as best response using extent of 
necrosis in the treated lesions over all follow up visits 
• 
Hepatic progression free survival will be measured from first treatment until 
progression occurring in the liver, as defined by RECIST criteria 
• 
Change in tumor markers (CA 19-9) will be measured throughout the study 
• 
Overall survival will be determined by telephone follow-up after 12 months 
1.18   Statistical 
Considerations 
54 subjects will be enrolled into the study and randomized to combination therapy 
or systemic therapy in a 1:1 fashion. Subjects exhibiting complete or partial response 
will be classified as responders and all other subjects as non-responders. The 
response rate in the intravenous chemotherapy group can be assumed to be 25% and 
we expect to see response rates of 70% in the chemoembolization with LC or 
ONCOZENE beads loaded with Irinotecan group.  The sample sizes in the table 
provide 80% power for a Fisher’s exact test to detect the given difference between 
the assumed proportions at a significance level of 0.05. 
1.19   Endpoints 
 
Proportion of subjects completing scheduled treatment plan  
 
Safety: Serious adverse events and Dose limiting toxicities  
 
Efficacy:   Response to Treatment and Survival 


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2 Investigational Plan 
 
2.1 
Study Objectives 
 
The primary objective of this study is to evaluate the safety and efficacy of LC beads, loaded 
with Irinotecan, or the ONCOZENE beads, loaded with Irinotecan, in combination with 
intravenous chemotherapy versus intravenous chemotherapy alone in the treatment of 
unresectable intrahepatic cholangiocarcinoma. 
 
2.2 
Study Design 
 
This is an open label, prospective, randomized, controlled phase II study designed to 
assess the clinical performance of chemoembolization with LC or ONCOZENE beads, 
loaded with Irinotecan, in combination with Gem-Cis or Gem-Carbo intravenous 
chemotherapy versus Gem-Cis or Gem-Carbo intravenous chemotherapy alone in the 
treatment of unresectable intrahepatic cholangiocarcinoma. 
 
2.3 
Primary Endpoint 
 
The primary endpoint will be tumor response according to modified RECIST Criteria. 
 
2.3.1 Tumor Response 
 
Prior to 1994, the assessment of antitumor effect of a treatment was generally 
determined in accordance with the World Health Organization (WHO) criteria 
established in the late 1970s. The WHO criteria assess the change in tumor size 
using two perpendicular measurements of lesions. 
 
The WHO criteria were reviewed in the 1990s leading to the development of a new set 
of criteria called Response Evaluation Criteria in Solid Tumors (RECIST).41 RECIST 
considers the change in tumor size using the sum of uni-dimensional measurements of 
the longest diameter in up to five target lesions per organ (or ten in total, representing 
all involved organs) and also accounts for non-measurable lesions. Since then it has 
been modified with the recent publication taking into account changes in vascularity.  
Similarly, metastatic colorectal cancer response is more commonly assessed by PET 
scan and reduction in Standardized Uptake Values (SUV) counts. This protocol will use 
both the modified RECIST criteria and PET scan intensity to evaluate liver specific 
response and extra-hepatic disease response. 
 
2.3.1.1 
Modified RECIST Criteria 
 
Modified RECIST is currently accepted as the basis for assessing antitumor 
activity in all solid tumor types and is endorsed by regulatory authorities.42 
 
2.3.1.1.1 Measurement and identification of target lesions 
 
Subjects must have at least one measurable lesion, defined as >20 mm 
using CT or MRI or >10 mm using spiral CT. When disease is restricted 
to a solitary lesion, its neoplastic nature must be confirmed by 
cytology/histology. 
 
Baseline measurements must be taken within four weeks prior to 
commencement of treatment. The same measurement technique (CT/MRI) 
must be used at baseline and follow up. No more than 5 target lesions in 
the liver and 10 lesions in total, representative of all sites involved, 
will be identified. Those with the largest diameters should be included. 


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All other (non-target) lesions should be reported but not measured, in 
order that their presence or lack thereof may be tracked at follow up. 
 
2.3.1.1.2 Criteria for target lesions 
 
Complete 
Response: 
Disappearance of all target lesions or disappearance of 
all arterial enhancements in the target lesion 
Partial 
Response: 
At least 30% decrease in the sum of the longest diameter 
of target lesions, taking as reference the baseline sum of 
longest diameter, or ≥30% loss of arterial enhancement 
Progressive 
Disease: 
At least 20% increase in the sum of the longest diameter 
of target lesions, taking as reference the smallest sum of 
the longest diameters recorded since start of treatment, 
OR appearance of one or more new lesions 
Stable 
Disease: 
Neither sufficient shrinkage to qualify for partial response 
nor sufficient increase to qualify for progressive disease, 
taking as reference the smallest sum of the longest 
diameters recorded since start of treatment 
 
2.3.1.1.3 Criteria for non-target lesions 
 
Complete 
Response: 
The disappearance of all non-target lesions 
AND normalization of tumor marker level 
Incomplete 
Response/Stable 
Disease: 
Persistence of one or more non-target lesions AND/OR 
maintenance of tumor marker level above normal limits 
Progressive 
Disease: 
Appearance of one or more new lesions AND/OR 
unequivocal progression of existing non-target lesions 
(progression of non-target lesions will be determined at 
the investigator’s discretion) 
 
2.3.1.1.4 Response evaluation and reporting 
 
Tumor response will be evaluated at approximately 10 weeks by 
abdominal CT/MRI following the first round of treatments (3 total cycles 
of chemotherapy). Tumor response will again be evaluated by abdominal 
CT/MRI following any additional rounds of treatment (3 cycles 
increments of chemotherapy) and/or at approximately 10 week (if dose 
limiting toxicities 
are 
experienced). 
After 
study treatment 
is 
discontinued, tumor response will be evaluated every 3-4 months for a 
total of 12 months post-last active study treatment. After each 
radiographic evaluation, response in target and non-target lesions along 
with presence of any new lesions will be reported on the CRF. Overall 


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response will be assigned by combining the response in target lesions, 
non-target lesions, and the appearance or lack of new lesions as outlined 
in the table below. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
2.3.1.1.5 Evaluation of best overall response 
 
The best overall tumor response (according to modified RECIST) is 
defined as the best response from start of treatment over all follow up 
visits or until disease progression/recurrence whichever comes first. 
 
2.4 
Secondary Endpoints 
 
The secondary endpoints will include: 
 
 
Local tumor response (extent of necrosis in the treated lesions) 
 
Time to progression 
 
Hepatic Progression Free Survival 
 
Change in tumor markers 
 
Overall survival 
 
Patient Tolerance 
 
2.4.1 Subject Tolerance 
 
Safety assessments will include physical examinations, vital signs, clinical laboratory 
profile and adverse events. 
 
All observed toxicities and side effects will be graded according to NCI Common 
Toxicity criteria v.4.0 toxicity criteria for all subjects and the degree of association of 
each with the procedure assessed and summarized. 
 
Treatment related Serious Adverse Events rate (SAE) — defined as SAEs considered 
possibly, probably or definitely related to treatment — will be determined. 
 
2.4.1.1 
Response evaluation and reporting 
 
Tumor response will be evaluated by CT/MRI after every third cycle of 
systemic chemotherapy at approximately 10, 20, and 30 weeks following the 
first treatment. The primary efficacy time point will be after the 10-week 
visit. At each follow-up visit that requires CT/MRI evaluation, the diameter, 
percentage necrosis and viable diameter for each target lesion will be reported 
in the CRF. 


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2.4.1.1.1 Evaluation of best overall response 
 
The best overall response is defined as the best response from start of 
treatment over all follow-up visits or until disease progression/recurrence. 
 
The protocol acknowledges that this assessment of local tumor response 
is not a validated method, but will provide useful information on the 
assessment of necrosis following locoregional treatment with LC or 
ONCOZENE beads loaded with Irinotecan. 
 
2.4.2 Time to Progression 
 
Overall time to progression to include all hepatic disease and extra-hepatic disease 
will be recorded to assess both organ specific and systemic response rates between 
both treatment arms. 
 
2.4.3 Time to Liver Progression 
 
Liver specific time to progression will also be recorded to better assess the response 
rates and duration of response to combined liver directed therapy when compared 
with systemic therapy alone. 
 
2.4.4 Change in Tumor Markers 
 
CA 19-9 and will be measured at baseline and every 3 months. Values will be 
assessed for clinical significance. 
 
2.4.5 Overall Survival 
 
Overall survival will be determined using Long-Term Follow-up visits and/or by 
telephone or standard physician follow-ups as per standard of care until death. 
 
2.5 
Study Population 
 
2.5.1 Number of Subjects 
 
Up to 54 subjects will be enrolled. These subjects will be randomized into group 1: 
Gem-Cis or Gem-Carbo systemic chemotherapy only group (Control Group) or 
group 
2: 
Gem-Cis 
or 
Gem-Carbo 
systemic 
chemotherapy 
plus 
chemoembolization with LC or ONCOZENE beads (Test Group) (1:1 in each arm). 
 
2.5.2 Selection Criteria 
 
Subjects will be eligible for the study if they fulfill the following entry criteria. 
 
2.5.2.1 
Inclusion Criteria 
 
• 
Subjects over 18 years of age, of any race or sex, who have histological 
evidence of intrahepatic cholangiocarcinoma, who have been deemed 
unresectable by an experienced hepatic surgeon, able to give informed 
consent 
• 
Subjects with at least one measurable liver metastases, with size > 1cm 
(modified RECIST criteria) 
• 
Subjects with liver-dominant disease, defined as ≥80% of the subject’s total 
amount of malignant disease (tumor burden) that is confined to the liver 


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• 
Fertile men and non-pregnant women of childbearing potential who have 
agreed to use an acceptable method of birth control. Women of child bearing 
potential must have a negative βHCG (serum or urinalysis) to be eligible. 
• Hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 75 x109/L, INR ≤1.3 
(subjects on therapeutic anticoagulants are not eligible if they cannot stop 
their anti-coagulation prior to DELTIC and meet INR criteria) 
• 
Adequate liver function as measured by: Total bilirubin ≤ 2.0 mg/dL, AST 
and ALT ≤ 5 ULN, albumin ≥ 2.5 g/dL 
• 
Adequate renal function as measured  by:  Creatinine  ≤  2.0  mg/dl,  >  50 
ml/min calculated by the C-G equation 
• 
Signed, written informed consent 
• 
ECOG status ≤ 2 
• 
Liver tumor volume less than 70% of total volume of the subject’s liver (i.e. 
less than 70% tumor replacement) 
 
2.5.2.2 
Exclusion Criteria 
 
• Subjects eligible for curative treatment (i.e.  resection  or  radiofrequency 
ablation) 
• Active, untreated bacterial, viral or fungal infection within 72 hours of study 
entry 
• Women who are pregnant or breast feeding 
• ECOG Performance Status score of ≥3 
• Life expectancy of < 3 months 
• PTT > 2.5 ULN and Hgb < 8.0 mg/dL 
• Patients with a history of Gilbert’s Syndrome 
• Patients with a history of UGT1A1 deficiency 
• Allergy to contrast media that cannot be managed with standard care (e.g. 
steroids), making magnetic resonance imaging (MRI) or computed 
tomography (CT) contraindicated 
• Presence of another malignancy with the exception of cervical carcinoma in 
situ and stage I basal or squamous carcinoma of the skin 
• 
Any contraindication for hepatic embolization procedures: 
- 
Large shunt as determined by the investigator (pretesting with TcMMA 
not required) 
- 
Severe 
atheromatosis 
vascular 
disease 
that 
precludes 
arterial 
cannulization 
- 
Hepatofugal blood flow 
- 
Main portal vein occlusion (e.g. thrombus or tumor) 
• 
Other significant medical or surgical condition, or any medication or 
treatment, that would place the subject at undue risk and that would preclude 
the safe use of chemoembolization or would interfere with study participation 
• 
Subjects with prior contraindications for the use of Irinotecan, gemcitabine,  
Cisplatin or Carboplatin 


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• 
Subjects who have received prior systemic therapy with either Irinotecan, 
gemcitabine, Cisplatin or Carboplatin 
• 
Subjects taking medications that may counteract the study medications. These 
medications include CYP3A4 inducers such as Rifabutin, and St. John’s Wort, 
and CYP3A4 inhibitors such as Ketoconazole. 
 
2.6 
Study Procedures and Methodology 
 
2.6.1 Study Schedule and Guidelines for Visits 
 
Subjects admitted for first line chemotherapy for unresectable intrahepatic 
cholangiocarcinoma will be reviewed for study eligibility. After checking suitability 
to enter the study, subjects who agree to participate must sign the informed consent 
form before undergoing any study related procedures or treatment. 
 
2.6.1.1 
Baseline Assessment 
 
Occurs within four weeks of the first treatment: 
 
o Detailed medical history including previous cancer history and cancer 
treatment. Any concomitant medications taken up to 30 days prior to the 
first study treatment will be recorded. 
o Physical examination including weight, height and vital signs (height 
will be collected at baseline only) 
o Laboratory tests CBC and CMP; tumor markers: CA 19-9; and 
coagulation (baseline and as clinically indicated): P 
o Demographics 
o Pain score-graded using a standard ten point pain scale 
o Performance Status (ECOG) 
o Serum pregnancy test (for women of child bearing potential) 
o Documentation of disease status: 
o All sites of disease should be identified by dynamic MRI or 
contrasted CT of abdomen/pelvis as well as contrasted CT 
chest and recorded at baseline. At least one measurable hepatic lesion 
must be identified as target lesion and measured. This scan will be 
performed within 4 weeks prior to first treatment. 
The investigator will confirm the subject’s eligibility after all baseline scans 
and laboratory results have been reviewed. 
 
 
 
 
 
 
 
Eligible patients with 
unresectable intrahepatic 
cholangiocarcinoma 
Treatment Arm A 
 
Standard Chemotherapy Only 
                                      Gem/Cis or Gem/Carbo cycle q 3 weeks 
 
     
 
Treatment Arm B 
LC or ONCOZENE Beads plus Standard 
Chemotherapy 
 Beads q 3 weeks starting on Week 1  
Chemo cycle q 3 weeks starting on Week 2  


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Page 15 of 48 
 
2.6.1.2 
Treatment Period 
 
2.6.1.2.1 TEST GROUP 
 
Subjects randomized to the Test Group will receive chemoembolization 
with the Irinotecan loaded LC beads or the Irinotecan loaded 
ONCOZENE beads plus systemic chemotherapy consisting of 
Gemcitabine/Cisplatin or Gemcitabine/Carboplatin in the following 
fashion: 
 
• 
Chemoembolization with Irinotecan loaded beads (LC or 
ONCOZENE) performed every 3 weeks, starting on Week 1.* 
• 
Cisplatin at 25 mg/m2 given as a 2-hour IV infusion on Days 1 
and 8, starting on Week 2.  
OR 
• 
Carboplatin dose (mg) = (target AUC) x (GFR + 25) with target 
AUC = 4 given as a 2-hour IV infusion on Day 1 only starting on 
Week 2. The maximum dose for AUC of 4 is 600 mg. 
AND 
• 
Gemcitabine at 1000 mg/m2 given as a 30-minute IV infusion 
following Cisplatin on Days 1 and 8, starting on Week 2. 
 
If the treating medical oncologist feels that Cisplatin is not recommended 
for the subject based on performance status or tolerance then Cisplatin 
can be replaced with Carboplatin on a case by case decision with the 
Sponsor.  The Carboplatin dose will be based on a Target Area Under the 
Curve of 4 using the Calvert Formula of Total Carboplatin Dose (mg) = 
Target AUC x (GFR+25).  The maximum dose for AUC of 4 is 600 mg. 
 
The first chemotherapy treatment will occur one week after the first 
chemoembolization procedure and will occur during Week 2 of the study 
calendar. Each chemotherapy cycle is repeated every 3 weeks (21 days). 
 
All doses will be based on the subject’s actual weight. The actual weight 
at screening will be used to calculate body surface area (BSA). Some 
institutions may have a BSA maximum of 2.0 which may be used; 
however, the BSA should be recalculated if a subject’s weight changes 
by ≥10%. 
 
All treatment regimens will be given until progression of disease or until 
the treating physician determines it is in the subject’s best interest to 
discontinue therapy. 
 
* It is anticipated that each subject randomized to the Test Group will 
receive two chemoembolizations (minimum 3 weeks apart) during 
their treatment period. Subjects in the Test Group may receive 
additional chemoembolizations, if needed. Guidance for repeat 
treatments is at the treating physician’s discretion and based on the 
subject’s response and tolerance to treatment along with the subject’s 
overall burden of disease. With chemoembolization procedures, it is 
routine care to assess a subject’s tumor response using CT or MRI 
imaging every 10-12 weeks. These intervals are long enough to reflect 


3/30/2017 version (Amendment 5) 
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Page 16 of 48 
 
the amount of tumor necrosis and short enough to reveal tumor 
recurrence or progression. 
 
2.6.1.2.1.1 
Irinotecan DEB 
 
The Test Group will receive chemoembolization using Irinotecan- 
loaded LC Beads, using up to 2 mL of Irinotecan-loaded LC beads 
(bead size: 70-150 μm or 100-300 micron; 100mg Irinotecan) or 
Irinotecan-loaded ONCOZENE beads, using up to 2 mL of 
Irinotecan-loaded ONCOZENE beads (bead size: 40 µm or 75 µm; 
100 mg Irinotecan). 
 
The following assessments will be made within 24 hours prior to LC 
or ONCOZENE bead chemoembolization procedure: 
 
• 
Vital signs 
• 
Physical Exam / Nursing Assessment 
• 
Laboratory   Tests   (CBC, CMP, magnesium)   (may   be 
performed up to 72 hours prior) 
• 
Adverse Event Monitoring 
• 
Concomitant Medication monitoring 
 
2.7 
Chemoembolization Procedure 
 
The following procedures will be followed for each chemoembolization treatment. 
 
2.7.1 Pre Treatment 
 
The subject should be nil by mouth overnight prior to the treatment. Subjects will be 
adequately pre-medicated according to standard hospital procedure. Subjects will 
have a venous line inserted prior to therapy and hydration will be scheduled 
according to clinical needs. Analgesics, anti-emetics and prophylactic antibiotic 
therapy will be given at the discretion of the investigator except for aprepitant and 
dexamethasone which should be dosed according to this protocol. 
 
Due to potential drug-drug interactions, the use of aprepitant (Emend) and 
dexamethasone (Decadron) for antiemetic therapy should be assessed and 
appropriate substitutes considered for ALL subjects randomized to the 
Treatment Group and receiving chemoembolizations. 
However, if alternative medications are not felt to be adequate for controlling 
the side effects of chemotherapy, the CAUTIOUS use of these drugs may be 
clinically warranted. This determination will be based on the treating physician’s 
discretion and should be reflected in the AEs and SAEs for the subject. If these 
drugs are utilized, the AEs and SAEs for the subject will need to be followed 
with additional focus looking for any effects of potential drug interactions. 
Aprepitant (Emend) and dexamethasone (Decadron) should be dosed in the 
following fashion: 
• Aprepitant 125 -150 mg intravenously with chemotherapy 
infusion 
• Dexamethasone 10-12 mg intravenously with chemotherapy 
infusion 
 
2.7.2 Pain Management 


3/30/2017 version (Amendment 5) 
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Page 17 of 48 
 
 
In prior studies of chemoembolization with LC beads loaded with Irinotecan, all 
subjects reported moderate post procedural pain. It is recommended that a strong 
opioid (e.g. Morphine) parenteral be used for the procedure. Intra-arterial lidocaine 
(2-4cc) prior to injection of loaded beads may be used at the investigator’s discretion. 
 
2.7.3 Loading Procedure for LC or ONCOZENE Beads Loaded with Irinotecan 
 
The instructions are for a dose of up to 100 mg of Irinotecan to be delivered in 1 vial 
of LC or ONCOZENE beads at a dose of 50 mg/mL of LC beads or ONCOZENE 
beads. Irinotecan is available as Campto solution at 100mg/vial (5 mL at a 
concentration of 20 mg/mL), and it is these vials that are recommended for use. 
 
 
Irinotecan Dose 
Required 
Volume of Bead 
Required 
Volume of Bead vials, containing 2 
mL of Beads 
100 mg 
2 mL 
1 vials 
The instructions are to load 100 mg Irinotecan into 1 vial containing 2 mL of LC 
or ONCOZENE beads at a dose of 50 mg per mL of LC or ONCOZENE beads. 
 
2.7.3.1 
Preparation of LC or ONCOZENE Bead 
 
Remove as much saline as possible from each vial of beads using a 
syringe with a small gauge needle or filter needle. This step usually takes 
5- 10 minutes depending on experience. 
2.7.3.2 
Loading of LC or ONCOZENE Bead 
 
Using a syringe and needle add a total of 5 mL of Campto solution (20 
mg/mL) directly into each vial of beads. 
 
Agitate the beads/Campto solution gently to encourage mixing then allow 
the solution to stand until beads are loaded. The LC beads will appear 
turquoise and the ONCOZENE beads will appear red when the 
loading is completed. For this static loading the following times should be 
used to give at least 90% loading of the dose into LC or ONCOZENE beads: 
 
 
Product Cap 
Color 
Nominal Size 
Range (µm) 
Time to give 
>90% Loading 
Actual Amount 
Loaded 
Yellow 
100-300 
2 h 
98% 
Black and Yellow 
70 - 150 
2 h 
98% 
Black 
40 
30 minutes 
98% 
Maroon 
75 
30 minutes 
98% 
 
After loading, LC and ONCOZENE beads should be stored at room 
temperature or refrigerated.  Transfer the vials of loaded beads to Radiology 
when requested. 
 
 
2.7.3.3 
Preparation for Use 
 


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Prior to use, transfer the LC or ONCOZENE beads loaded with Irinotecan 
to a 20 mL syringe and add an equal volume of non-ionic contrast media 
[~7 mL (5 mL of Campto + 2 mL of beads)]. This step will take 2-15 
minutes again depending on experience. Invert the syringe gently and wait 
1 to 15 minutes to obtain an even suspension of LC or ONCOZENE beads. 
 
Contrast media should be added immediately prior to use. 
 
2.7.3.4 Similarity of Both Beads: 
 
ONCOZENE microspheres are FDA cleared (Registration# K130307) as a 
Class II device (Product Code: KRD) for the “embolization of hypervascular 
tumors and arterial-venous malformations”. This is the same FDA indications 
as Quardaspheres (Merit Medical) and LC Beads (Biocompatibles). As with 
the competition microspheres drug loading and delivery are “Off label” 
indications.  
ONCOZENE/ONCOZENE microspheres are hydrogel core, flexible and 
compressible polymer microsphere with a polymethacrylate backbone 
surface coated with a thin (nm) shell of PolyzeneÒ-F coating (high molecular 
weight, ultrapure, biocompatible polymer of polyphosphazene).  They are 
unique in that they come in three sizes (40 ± 10 μm; 75 ± 15 μm; and 100 ± 
25 μm) and are the smallest available microspheres for DEB-TACE (Drug-
Eluting Bead-Transarterial Chemoembolization). Small drug eluting 
microspheres have been reported to cause a higher degree of tumor necrosis.  
ONCOZENE/ONCOZENE microspheres can load drugs faster than the 
competition (doxorubicin powder made to 20 mg/ml solution loads in 1 hour, 
and irinotecan solution loads in 30 minutes).  The microspheres can load more 
doxorubicin per ml microspheres (50 mg/ml versus 37.5 mg/ml for LC Beads 
or LC M1)(2 ml syringe of ONCOZENE Microspheres can load 100 mg 
doxorubicin, does not need 2 unit of competition device to deliver 100 mg) . 
This is 33% more deliverable drug unit.  They are stable after drug loading 
which equates to no microsphere shrinkage. 
In vitro drug release time for ONCOZENE/ONCOZENE microspheres is 
slower than reported competition in vitro release rates. Therefore, slower drug 
elution causes lower systemic drug levels and slower drug elution can cause 
prolonged and higher drug tissue concentrations. For Irinotecan used in 
treating mCRC, in animal studies using a VX2 tumor model, ONCOZENE-
irinotecan showed reduced systemic exposure to Irinotecan, higher and 
prolonged tumor drug concentration, and higher necrosis versus IA and IV 
administration.  
ONCOZENE/ONCOZENE microspheres come in convenient 2 ml or 3 ml 
syringes that can load and deliver 100 mg to 150 mg of the desired drug via 
trans-arterial embolization of the tumor(s) lesions.  
ONCOZENE microspheres have been used in Europe to treat HCC. 
ONCOZENE microspheres (3 ml syringe loaded with 150 mg doxorubicin) 
have been administered to patients with the following results: 
o 17 patients underwent 33 DEB-TACE procedures with no treatment 
related deaths  


3/30/2017 version (Amendment 5) 
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Page 19 of 48 
 
o Embolizations were to stasis in all 2o segmental arteries.  
o Post-embolization syndrome (PES) was reported in 8 out of 33 
procedures (25%) which is lower than traditional Deb-
TACE.  Other adverse events (10 out of 33) were Grade II or lower. 
o Initial tumor control at 4 weeks was 100% (17/17) and at 12 weeks 
(6/7 = 86%). This study is ongoing.  
A case report using ONCOZENE-Irinotecan is below. Andreas Saleh, MD., 
Institute for Diagnostic and Interventional Radiology and Infant Radiology, 
Clinical Center of Schwabing, Germany treated 2 patients with ONCOZENE-
IRI.  
o Patient #1: A 60 year old patient with reoccurring mCRC at resection 
edge was treated with ONCOZENE-IRI (40 μm loaded with 37.5 mg 
irinotecan). At follow-up (5 months) tumor is in regression with no 
revascularization.   
o Patient #2: A 72 year old patient with reoccurring pulmonary and 
liver metastases, with resection of pulmonary metastases (3 months 
before DEB-TACE), was treated with ONCOZENE- IRI (1.3 ml of 
ONCOZENE-IRI, loaded with 67 mg irinotecan in 1.3 ml). 
Immediate 
post 
embolization 
fluorography 
showed 
total 
devascularization of the lesion. 6 month CT showed no reoccurrence 
of tumor.  
ONCOZENE-IRI has been used in the U.S. at several institutions. There are 
no published reports to date. Anecdotal information included the following:  
o 100 μm ONCOZENE microspheres loaded with 100 mg of Irinotecan 
have been used with no reported severe adverse events other than 
PES pain which has ranged from none to requiring overnight 
opioids.  Treatment were lobar and sub-selective.  
o Reports are that a single treatment has reduced tumor vascularization 
and stable disease to complete reduction of tumor lesion.  
o The overall systemic exposure of Irinotecan from the ONCOZENE™ 
bead is similar to reduced when compared to the DEBIRI bead. 
 
ONCOZENE-IRI versus DEBIRI in Animal Models and Humans 
Model 
Device 
IRI 
Dose 
Plas
ma 
TMAX 
Plasm
a 
CMAX 
[ng/ml] 
Plasm
a T1/2 
AUC 
ng•hr/ml 
Ratio 
AUCD
EB 
AUCIV 
(% 
↑or↓) 
[Tissue] 
ng•hr/m
l 
Reference 
Sheep 
DEBIRI 
(DC 300-
500µm) 
50 mg 
5 
min 
663 
∼1.0 
hr 
56862 
0.410 
59% ↓ 
See 
below 
Baylatry et 
al. 2011.  J 
Biomed 


3/30/2017 version (Amendment 5) 
DELTIC study 
Page 20 of 48 
 
Mat Res B:  
App 
Biomat.  
99B:351 
 
 
 
 
 
 
 
 
 
 
Rabbi
t VX2 
DEBIRI 
(Pre-loaded 
DC 100-300 
µm with 100 
mg IRI/ml 
rehydrated 
microspheres) 
6-16.5 
mg 
(Dosed 
to 
stasis, 
so each 
tumor 
received 
a 
differen
t 
amount 
of drug) 
10 
min 
189.7 
4.1 hr 
79390-2 hr 
184682-24 
hr 
(ng•min/
ml) 
ND 
See 
below 
Rao et al. 
2012.  
Cardiovas 
Intervent 
Radiol. 
35:1448 
ONCOZENE-
IRI 
(40 µm 
ONCOZENE 
) 
(50 or 25 mg 
IRI/ml 
microspheres) 
4.2 mg 
60 
min 
172 
3.16 
hr 
2158* 
0.034 
96%↓ 
See 
below 
Internal 
data 
8.33 mg 
30 
min 
351 
3.15 
hr 
4656* 
0.073 
93% ↓ 
 
 
 
 
 
 
 
 
 
 
Pig 
DEBIRI 
(DC100-300 
µm) 
200 mg 
(25, 50, 
100, or 
200 mg 
IRI) 
2 
min 
1791 
∼3.5 
hr 
ND 
0.99+
+ 
ND 
Taylor et al.  
2007. Eur J 
Pharmaceuti
cal Sci. 
30:7-14 
DEBIRI 
DC100-300 
µm pre-
loaded 
with100 mg 
IRI/ml 
lyophilizedbe
ads) 
100 mg 
10 
min 
1532  
3.35 
hr 
7307** 
1.11≡ 
11%↑ 
ND 
Lewis et al.  
2013. J Mat 
Sci: Mater 
Med.  
24:115-127 
ONCOZENE-
IRI 
75 µm 
50 mg 
20 
min 
95.6 
2.45 
hr 
39295* 
0.106 
89%↓ 
See 
below 
Just 
completed  
Internal 
data 
DEBIRI  
(DCM1 70-150 
µm) 
 
 
50 mg 
10 
min 
170.9 
1.3 hr 
49722* 
0.134 
87%↓ 
See 
below 
 
 
 
 
 
 
 
 
 
 
Huma
n 
DEBIRI 
100-400 
mg 
2 hr 
194 
4.6 hr 
1680        ND 
ND 
Eichler et 
al.  2012. 
Internat J 


3/30/2017 version (Amendment 5) 
DELTIC study 
Page 21 of 48 
 
Oncology.  
41:1213-
1220 
DEBIRI 
100 mg 
1 hr 
281 
∼4 hr 
ND 
ND 
ND 
Martin et al. 
2012. J 
Gastrointest 
Surg.  
16:1531 
 
ND = not determined 
TMax = Time to Maximum Drug Concentration 
CMAX= Maximum Irinotecan Plasma Concentration 
T1/2 = Time to Reduce Irinotecan Concentration in Half  
AUC = Area Under the Curve 
* AUC Calculated assuming a bolus injection of irinotecan 
** Not sure AUC is calculated the same way as Radeleff and Tanaka 
≡ AUC calculation was not over total time frame, and is not truly comparable to Tanaka.  
++ estimated from Figure 4A. 
 
 


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Page 22 of 48 
 
ONCOZENE-IRI and DEBIRI Drug Concentrations in Analyzed Tissues 
 
Model 
 
 
Device/Dose 
[Tissue/Tumor irinotecan Concentration] 
ng•hr/ml 
Sheep 
DEBIRI 
4 days = no detectable irinotecan or SN 38 
28 days = no detectable irinotecan or SN-38 
 
 
 
Rabbit VX2 
(Rao et al) 
DEBIRI 
(DC 100-300 µm 
pre-loaded with 
100 mg IRI/ml) 
6-16.5 mg 
(Dosed to stasis, 
so each tumor 
received a 
different amount 
of drug) 
1 hr= 20.225 ng/g tissue irinotecan 
6 hr = 42.08 ng/g tissue irinotecan 
24 hr = 174.44 ng/g tissue irinotecan 
 
1 hr= 1.95 ng/g tissue SN-38 
6 hr = 4.65 ng/g tissue SN-38 
24 hr = 70.25 ng/g tissue SN-38 
Rabbit VX2 
(Internal Data) 
ONCOZENE-
IRI 
40 µm 
ONCOZENE 
 
Group 1 = 3.42 
mg IRI 
Group 2 = 1.71 
mg IRI 
Group 3 = 1.71 
mg IRI 
Group 1 24 hrs = 2842 ng/g tissue irinotecan 
Group 2 24 hrs = 857 ng/g tissue irinotecan 
Group 3  24 hrs = 1049 ng/g tissue irinotecan 
 
Group 1 72 hrs = 66 ng/g tissue SN-38 
Group 2 72 hrs = 25 ng/g tissue SN-38 
Group 3  72 hrs = 12 ng/g tissue SN-38 
 
 
 
Pig 
(Internal Data 
DCM1 was used 
as a control) 
ONCOZENE-
IRI 
(75 µm 
ONCOZENE) 
 
50 mg 
24 hr = 680 ng/g tissue irinotecan 
48 hr = 143 ng/g tissue irinotecan 
72 hr = 130 ng/g tissue irinotecan 
168 hr =  91 ng/g tissue irinotecan 
 
24 hrs = 86.4 ng/g tissue SN-38 
48 hrs = 37.5 ng/g tissue SN-38 
Pig 
(Internal Data) 
DEBIRI 
(DCM1 70-150 µm) 
 
50 mg 
24 hr = 832 ng/g tissue irinotecan 
48 hr = 142 ng/g tissue irinotecan 
72 hr = 141 ng/g tissue irinotecan 
168 hr =  142 ng/g tissue irinotecan 
 
24 hrs = 52.5 ng/g tissue SN-38 
48 hrs = 0.0 ng/g tissue SN-38 
 
 
 
 
 
 
 
 
 
 


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Study # 1 
Pig liver embolization with 75 µm ONCOZENE versus DCM1 (70-150 µm) 
 
1. ONCOZENE is slower to release Irinotecan than DCM1. 
2. Initial plasma levels of ONCOZENE-irinotecan are 2-3 times lower than DCM1. 
3. Much higher SN-38 Tissue concentrations for ONCOZENE at both 24 and 48 hrs.   
4. SN-38 is active form of Irinotecan and is converted intra-cellularly by 
carboxylesterase converting enzyme (CCE) in liver or colorectal tissue. 
Working Hypothesis: 
Irinotecan is activated via intra-cellular enzymes to SN-38 to be most effective in 
killing tumor/tissue.  The reason that there is detectable levels of SN-38 at extended 
time periods (48 hrs.) after ONCOZENE embolization is that embolization with 
ONCOZENE microspheres which penetrate deeper in the tissue’s micro-
vasculature, due to smaller, uniform sizes, improves microsphere distribution 
(better coverage).  The slower, controlled release of Irinotecan by ONCOZENE 
reduces systemic toxicities, and improves drug coverage, allowing for more 
localized enzyme activation of the irinotecan.  (e.g. Better embolization of the 
micro-vascular structures with significantly more particles (10 x 106 ONCOZENE 
microspheres/ml versus 1.2 x 106 DCM1 microspheres) increases the probability 
that Irinotecan can be converted to SN-38 which in turn should lead to better 
tumor/tissue killing). 
 
Study # 2  
VX-2 Rabbit Study: A Dose Response Study of 40μm Irinotecan-loaded 
ONCOZENE™ Microspheres using a Rabbit VX2 Liver Cancer Model 
 
Doses:  40 µm ONCOZENE 50 mg/ml microspheres or 40 µm ONCOZENE 25 
mg/ml microspheres 
 
Group 1 (3.42 mg irinotecan in 0.41 mls ONCOZENE) 
Group 2 (1.67 mg irinotecan in 0.20 mls ONCOZENE) 
Group 3 (1.563 mg irinotecan in 0.40 mls ONCOZENE) 
 


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Page 24 of 48 
 
 
 
 
Group 
AUC  for Serum 
Irinotecan 
Group 1 (3.42 mg Irinotecan) 
4656.5 ng•hr/ml 
Group 2 (1.67 mg Irinotecan) 
2158.3 ng•hr/ml 
Group 3 (1.63 mg irinotecan) 
2145.6 ng•hr/ml 
 
General Parameters 
Pharmacokinetic 
Parameter 
40 µm 
ONCOZENE-IRI 
 
 
 
Group 1 
Group 2 
Group 3 
CMAX 
 
351 ng/ml 
172 ng/ml 
180ng/ml 
Time to CMAX\ 
 
30 min 
60 min 
60 min 
T1/2 Beta Phase 
 
T1/2 =3.15 hrs. 
T1/2 = 3.16 hrs. 
T1/2 = 3.16 hrs. 
AUC Irinotecan 
Plasma 
 
4656.5 ng•hr./ml 
2158.3 ng•hr./ml 
2145.6 ng•hr./ml 
AUC SN-38 Plasma 
 
48.03 ng•hr./ml 
20.54 ng•hr./ml 
22.88 ng•hr./ml 
Tissue Irinotecan at 24 
hrs. ng/g Tumor 
2842 ng/g tissue 
857 ng/g tissue 
1049 ng/g tissue 
Tissue Irinotecan at 72 
hrs. ng/g Tumor 
66 ng/g tissue 
25 ng/g tissue 
12 ng/g tissue 
% Tumor Kill at 24 
hrs. 
 
90% Necrosis 
87% Necrosis 
90% Necrosis 
% Tumor Kill at 72 
hrs. 
 
70% Necrosis 
63% Necrosis 
65% Necrosis 


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% Tumor Kill at 168 
hrs. 
 
90% Necrosis 
93% Necrosis 
100% Necrosis 
AUC for Systemic bolus of 3.42 mg Irinotecan with T1/2 = 3 hrs = 
63527 ng•hr/ml 4656/63527 = 7.3% of injected Irinotecan 
 
 
 
Conclusions: 
1. Complete embolization using half dose IRI-loaded 40μm ONCOZENE (25mg IRI + 
2ml ONCOZENE) achieved high tumor necrosis rate. This result indicates that 
precisely calibrated 40μm ONCOZENE microspheres could have an advantage to 
effectively occlude the tumor feeding vessels, which could induce tumor ischemic 
necrosis.  
2. The liver dysfunction after TACE was significantly milder in the use of half dose IRI-
loaded 40μm ONCOZENE, when compared with the use of full dose IRI-loaded 
40μm ONCOZENE. In addition, the serum irinotecan concentration after TACE using 
half dose IRI-loaded ONCOZENE was significantly lower than that of full dose one. 
These results indicated that TACE using half dose IRI-loaded 40μm ONCOZENE 
could reduce the adverse effects in patients.  
3. T1/2 = 3.3 hrs  About right for animal with heart rate of 130+ beats/min 
4. Time to CMAX is extended, which implies slower drug release. 
5. Tissue irinotecan concentration remains above IC50 concentration for 72 hrs.  Indicates 
slow release into tissue and prolonged tissue presence due to ischemic with small 
microspheres. 
 


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Thus the ability to utilize either the BTG LC beads or the Celonova ONCOZENE 
beads will be similar with the desired effect of delivered Irinotecan to the target multi-
focal cholangiocarcinoma. 
2.7.4 Chemoembolization with LC or ONCOZENE Beads loaded with 
Irinotecan 
 
Subjects will receive chemoembolization using LC or ONCOZENE beads, loaded 
with Irinotecan. The size range for the LC beads to be used in the study will be 
70-150 µm or 100-300 µm (nominal) with a dose of up to 100 mg Irinotecan per 
treatment. The size of ONCOZENE beads to be used in this study will be 40 µm 
or 75 µm with a dose up to 100 mg Irinotecan per treatment.  No lipiodol will be 
used with LC and ONCOZENE beads, loaded with Irinotecan. The beads will be 
mixed with a non-ionic contrast media in the vial immediately prior to use 
according to the instructions for use.   
 
 
2.7.4.1 
Catheter Compatibility 
 
The following catheter or an equivalent or larger French size catheter 
is compatible with the LC or ONCOZENE beads loaded with Irinotecan. 
 
Trade Name 
Manufacturer 
Size 
Progreat
TM 
Micro Catheter 
System 
Terumo Corporation, 44-1, 2- Chome, 
Hatagaya, Shibuya-Ku, Tokyo 151-
0072, Japan 
2.4Fr 
Minimum outer diameter (O.D.) 
of 2.4Fr. (0.80mm) on the usable 
length of the catheter. 
 
2.7.4.2 
Embolization Procedure 
 
Vascular access is obtained via the common femoral artery and a guide wire 
advanced under fluoroscopic guidance. A diagnostic catheter is then inserted 
over the guide wire. The superior mesenteric artery is selected and an 
angiogram performed to identify any aberrant arterial anatomy and verify 
ante grade portal vein flow. The celiac axis is then selected and an angiogram 
is performed. A microcatheter is advanced coaxially through a diagnostic 
catheter for super selective arteriography of the hepatic arterial branches. The 
catheter and guidewire are used to select the proper hepatic artery and a 
limited angiogram performed to identify the branches of the hepatic artery. 
The right or left hepatic artery is selected distal to the cystic artery (if 
visualized), depending on the location of the lesions to be treated. 
 
Once the vascular supply of the tumor is identified, chemoembolization of 
the supplying artery may be performed. At the discretion of the 
interventional radiologist, extra hepatic vessels may be prophylactically 
embolized in order to mitigate risk of non-target deposition of LC or 
ONCOZENE beads, loaded with Irinotecan. Subjects with unifocal tumors 
will be treated with super-selective chemoembolization. At the discretion 
of the investigator, a micro catheter may be used to select a second or third-
order branch of the right or left hepatic artery in close proximity to the 
tumor. For multifocal disease or tumor spanning both lobes, a separate 
chemoembolization procedure will be performed for each lobe. These 
treatments will be performed in accordance with the study schedule. (e.g. 
right lobe chemoembolization performed on Week 1, left lobe 


3/30/2017 version (Amendment 5) 
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chemoembolization performed on Week 4) The goal is for drug delivery. No 
additional embolic agent will be given after infusion. 
 
Once the catheter is in place within the artery feeding the tumor, the LC 
or ONCOZENE beads, loaded with Irinotecan will be delivered into the 
artery. The objective of the therapy will be to deliver up to 2 mL (1 vial, 100 
mg Irinotecan) of 70- 150 µm or 100-300 µm LC beads or 40 µm or 75 µm 
ONCOZENE beads. Bead selection will be based on the size of the tumor(s) 
using the following criteria: 
 
• 
For multi-focal tumors < 2 cm, the 70-150 µm LC beads will be used 
or the 40 µm ONCOZENE beads will be used for the first treatment. 
 
• 
For all other tumors, the 100-300 µm LC beads will be used or the 75 
µm ONCOZENE beads will be used for the first treatment. 
 
• 
If however, the 100-300 µm LC beads or the 75 µm ONCOZENE 
beads cannot deliver at least 75% of the planned dose (because of 
pre-mature stasis), then this indicates these beads are too large for 
effective treatment.  Therefore, the smaller 70-150 µm LC beads or 
the 40 µm ONCOZENE beads may be used for subsequent treatments. 
 
Radiological non-ionic contrast (preferably Omnipaque or Visipaque) will be 
used to guide the injection of beads. The beads will be mixed with contrast 
(according to the instructions for use) immediately prior to the procedure and 
injected slowly in aliquots under careful fluoroscopic control. Standard 
precautions will be used for any subject who is taking Metformin and is 
receiving contrast media. These precautions include asking subjects to stop 
taking Metformin prior to the administration of the contrast and for 48 hours 
after the administration of the contrast media. A creatinine of > 2.3 mg/dl 
will be an exclusion to contrast administration. Catheter selection will be by 
operator preference (e.g. the choice of a microcatheter, in case of tortuous, 
narrow or spastic vessels). 
 
If vasospasm occurs, vasodilators may be given at the investigator’s 
discretion. If the vasospasm does not resolve, the procedure should be aborted 
and the subject rescheduled. 
 
The catheter will then be removed and homeostasis achieved by manual 
compression or closure device.  
 
The amount of contrast agent delivered to the subject during the procedure 
and dose of irradiation will be recorded as well as the time exposed to 
fluoroscopic imaging. The vessels embolized will be noted and the amount of 
embolic agent used will be recorded. All medications used during the 
procedure will be recorded, including pain management regime. 
 
2.7.4.3 
Embolization Endpoint 
 
The aim of the LC and ONCOZENE beads, loaded with Irinotecan 
embolization procedure will be to deliver the full dose of LC and 
ONCOZENE beads, loaded with Irinotecan (100 mg Irinotecan). The 
embolization endpoint will be until forward flow is reduced but avoiding 
backward flow of embolic agent that could result in embolization of vessels 
outside the liver. No additional embolic agent should be used to achieve the 


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embolization endpoint. 
 
2.7.5 Post Treatment 
 
Following the chemoembolization procedure all subjects will be observed for vital 
signs, femoral access site, pain management and fluid hydration. The procedure for pain 
management will be at the investigator’s discretion. 
 
Blood for other labs, such as CBC or blood chemistries and magnesium, may also be 
drawn on all subjects prior to discharge or 72 hours post-procedure. 
 
2.7.6 Discharge 
 
Upon discharge from the hospital, subjects will be given a suitable pain management 
regime based on normal hospital procedure, if needed. Details of the pain 
management regime will be recorded in the CRF. Written instructions for pain 
management will be given to subjects according to their clinical need. 
 
2.8 
Chemotherapy Cycles 
 
2.8.1 Control Group 
 
Control Group Subjects randomized to the Control Group will receive the standard 
systemic 
chemotherapy 
(Gem-Cis) 
or 
(Gem-Carbo) 
but 
without 
the 
chemoembolization procedures. 
 
If the treating medical oncologist feels that Cisplatin is not recommended for the 
subject based on performance status or tolerance then Cisplatin can be replaced with 
Carboplatin on a case by case decision with the Sponsor.  The Carboplatin dose will 
be based on a Target Area Under the Curve of 4 using the Calvert Formula of Total 
Carboplatin Dose (mg) = Target AUC x (GFR+25).  The maximum dose for AUC of 
4 is 600 mg. 
 
2.8.2 Treatment Group 
 
Subjects randomized to the Treatment Group will receive the standard systemic 
chemotherapy (Gem-Cis) or (Gem-Carbo) AND the chemoembolization procedures. 
 
If the treating medical oncologist feels that Cisplatin is not recommended for the 
subject based on performance status or tolerance then Cisplatin can be replaced with 
Carboplatin on a case by case decision with the Sponsor.  The Carboplatin dose will 
be based on a Target Area Under the Curve of 4 using the Calvert Formula of Total 
Carboplatin Dose (mg) = Target AUC x (GFR+25).  The maximum dose for AUC of 
4 is 600 mg. 
 
2.8.3 Chemotherapy Procedures 
 
The following procedures will be followed for each chemotherapy cycle for BOTH 
Control and Treatment Group subjects. 
 
 
 
 
 
2.8.3.1 
Pre-Treatment 
 


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Prior to each infusion, the following will be completed for all subjects: 
 
• 
Physical Exam or Nursing Assessment 
• 
Vital signs 
• 
Laboratory Tests (CBC, CMP, magnesium) 
• 
Adverse Event Monitoring and Concomitant Medication monitoring 
 
2.8.3.2 
Treatment 
 
The chemotherapy regimen will be given as Gem-Cis or Gem-Carbo standard 
chemotherapy with the same assessments and supporting care throughout each 
cycle. 
2.8.3.2.1. Supportive Treatment 
Supportive (non-protocol) treatment should be given when required, 
according to subject’s condition. Such supporting treatments include, but are 
not limited to: anti-emetics, hydration, pain relief, transfusions and growth 
factors.  
2.8.3.2.1.1.1. 
Anti-emetics 
All subjects should receive appropriate antiemetic therapy prior to each 
chemotherapy infusion.  
Due to potential drug-drug interactions, the use of aprepitant (Emend) 
and dexamethasone (Decadron) for antiemetic therapy should be 
assessed and appropriate substitutes considered for ALL subjects 
randomized to the Treatment Group and receiving chemoembolizations. 
However, if alternative medications are not felt to be adequate for 
controlling the side effects of chemotherapy, the CAUTIOUS use of 
these drugs may be clinically warranted. This determination will be 
based on the treating physician’s discretion and should be reflected in 
the AEs and SAEs for the subject. If these drugs are utilized, the AEs 
and SAEs for the subject will need to be followed with additional focus 
looking for any effects of potential drug interactions. 
Aprepitant (Emend) and dexamethasone (Decadron) should be dosed in 
the following fashion: 
• 
Aprepitant 
125 
-150 
mg 
intravenously 
with 
chemotherapy infusion 
• 
Dexamethasone 
10-12 
mg 
intravenously 
with 
chemotherapy infusion 
2.8.3.2.1.2. Hydration requirements 
 
Hydration guidelines may be added at the discretion of the physician 
to provide adequate Cisplatin or Carboplatin hydration to maintain 
renal function and urine output. However, the routine practice is to 
include at least 250 cc of NS before and after Cisplatin or Carboplatin 
administration. 
 
2.8.3.3 
Dose Modifications for Chemotherapy Treatment (Both Groups) 
 
In the event of chemotherapy-related toxicities, the recommended doses are 
detailed below. These lab values are based on the subject’s labs immediately 


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prior to a chemotherapy infusion. 
 
All toxicities should be graded according to Common Toxicity Criteria 
Adverse Events (version 4.0). 
 
2.8.3.3.1 Hematologic Toxicity 
• 
If treatment is delayed > 2 weeks due to hematologic toxicity, the 
subject’s active treatment will be discontinued. However, the 
subject will still be followed for toxicity and response. 
• 
ANC must be ≥ 1500/mm3 AND platelet count must be ≥ 
75,000/µL on Day 1 of each cycle 
• 
Dose reductions, once initiated, will remain permanent for all 
future cycles 
• 
Omitted Day 8 doses of Cisplatin or gemcitabine will not be made up. 
 
Absolute Neutrophil  
Count (ANC) (x106/L) 
Platelets 
(x106/L) 
% Full dose of 
Cisplatin or 
Carboplatin 
% Full dose of 
Gemcitabine 
≥ 1500 
≥ 75,000 
100% 
100% 
500 – 1499 
50,000 – 74,999 
75% 
75% 
< 500 
< 50,000 
0% 
0% 
 
2.8.3.3.2 Renal Toxicity (Cisplatin and Carboplatin only) 
 
Creatinine 
% Full dose of Cisplatin or Carboplatin 
≤1.5 x ULN 
100% 
≥ 1.5 but < 2 x ULN 
50% 
≥ 2 x ULN 
0% 
 
2.8.3.3.3 Hepatic Impairment 
 
Total 
Bilirubin(mg/dl) 
AST or ALT 
% of 
Full Dose 
≤ 1.5 
And 
<3X Upper Limit Normal 
100% 
1.5-1.9 
Or 
≤ ULN 
75% 
>1.9 
Or 
>5 ULN 
HOLD 
 
 
 
 
 
 
 
 
 
 
 
2.8.3.3.4 All Other Non-hematologic Toxicity 
 
• 
Chemotherapy will be held for < 2 weeks until recovery to 
Grade 1 or baseline (with exception of alopecia). 


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• 
If treatment is delayed > 2 weeks due to non-hematologic 
toxicity, the subject’s active treatment will be discontinued. 
However, the subject will still be followed for toxicity and 
response. 
 
2.9 
Follow-up Period Visits 
 
2.9.1 Long-Term Follow-up Period 
 
Subjects will be followed every 3-4 months for up to one year after discontinuation of 
active study treatment. The following information will be collected in subjects who 
have not had progression of disease: 
 
• 
Physical examination, including vital signs 
• 
Laboratory determinations (CBC, CMP, magnesium, CA19-9) 
• 
Radiological disease assessment 
 
After each CT or MRI, surgical resectability will be assessed to ensure that 
this treatment option is not withheld to any subject on study. 
 
2.9.2 Progression Free Follow-up Period 
 
Subjects who have completed the one year Long-Term Follow-up period will need to 
be evaluated every 3-6 months for radiologic disease assessment only until evidence 
of progression of disease. 
 
2.9.3 Overall Survival Follow-up 
 
Subjects who have evidence of disease progression will be followed for overall 
survival follow-up by telephone or standard physician follow-ups as per standard of 
care until death. 
 
2.9.4 Schema – See Attachment C 
 
2.10 End of Active Study Treatment 
 
Treatment in both arms of the study will only discontinue according to the protocol when 
the subject shows progression (i.e. lack of therapeutic efficacy) unless they fulfill any of 
the reasons for withdrawal (see Section 4 Study Termination). 
 
Additionally, subjects in the treatment arm who do not require or fail to receive a second 
or subsequent chemoembolization treatment should not necessarily be withdrawn from the 
study unless they fulfill any of the reasons for withdrawal. 
 
 
3 Adverse Events & Safety Monitoring 
 
3.1 
Adverse Event Recording and Evaluation 
 
All adverse events (AEs) must be recorded regardless of causal relationship. All AEs must 
be followed until resolved or until 30 days post last active study treatment. 
Anticipated adverse events will be differentiated from unanticipated adverse events. 
Anticipated events will be defined as the events listed in the LC Bead package insert and the 
ONCOZENE Microsphere package insert as potential complications and are included in 
subjects Informed Consents. 


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All unanticipated adverse events related to the device will be reported to the FDA within 
10 working days, as required per IDE regulation guidelines. In addition, all subject deaths 
occurring within 60 days of the last treatment will be reported to the FDA. 
To allow a standardized safety evaluation across centers and studies, assessment of the 
seriousness, intensity, outcome and causality of the AEs, should be undertaken by the 
Investigator using the CTCAE v4.0 criteria. 
 
3.1.1 Adverse Event Intensity 
 
The intensity of each AE must be assessed according to the grades defined in the 
CTCAE v4.0 classifications.  Each Grade refers to the severity of the AE. The CTCAE 
v4.0 displays Grades 1 – 5 with unique clinical descriptions of severity for each AE 
based on this general guideline: 
 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life threatening or disabling AE 
Grade 5 
Death related to AE 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
 
3.1.2 Adverse Event Treatment 
 
The treatment of each AE must be assessed according to the following 
classifications: 
 
None 
Subject did not receive any treatment for the AE 
Began/Changed 
Concomitant Medication 
New medical treatment was required to treat the AE 
Hospitalization/Prolonged 
Hospitalization 
Hospitalization or prolonged stay in the hospital 
was required due to the AE 
Other 
Any other treatment was required for the AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1.3 Adverse Event Outcome 
 
The outcome of each AE must be assessed according to the following classification: 
 
 


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Completely recovered: 
The subject has fully recovered with no 
observable residual effects 
Not yet completely recovered 
Improvement in the subject’s condition 
has occurred, but the subject still has 
some residual effects 
Deterioration 
The subject’s overall condition has 
worsened 
Permanent damage 
The AE has resulted in a permanent 
impairment 
Death 
The subject died due to the AE 
Ongoing 
The AE has not resolved 
Unknown 
The outcome of the AE is not known 
because the subject did not return for 
follow-up (lost to follow-up) 
3.1.4 Adverse Event Causality 
 
The causality of each AE must be assessed according to the following classification: 
 
• 
not assessable 
• 
not related 
• 
unlikely 
• 
possible 
• 
probable 
• 
definite 
 
3.2 
Reporting of Adverse Events 
 
Serious adverse events will be appropriately reported by the investigator to the local IRB 
according to local requirements.  
 
4 Study Termination 
 
4.1 
Early Stopping of Active Treatment Based on Toxicity 
 
4.1.1 Dose reduction and Early Stopping Based on Toxicity 
 
Notwithstanding the potential benefit of the treatment, if excess toxicity is observed as 
below, this would provide grounds for treatment modification, dose reduction or 
stopping the active study treatments earlier than planned. 
 
 
4.1.2 Dose Limiting Toxicities 
 
Dose limiting toxicities (DLT) will be defined as any Grade 4 toxicity (excluding 
nausea, vomiting, and recoverable hematologic toxicities) in more than 3 of each 10 
subjects enrolled. The treatment portion of the study would be stopped in the event 


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the device-related toxicity threshold is reached in more than 3 of 10 study subjects. 
 
Any death within 30 days of treatment on the protocol may be considered a DLT and 
may invoke a temporary hold in the study, while evaluating attribution. In addition, no 
more than five device-related deaths will be allowed during the trial. 
4.2 
Subject Withdrawal from Active Study Treatment 
 
Subjects may be withdrawn from the active treatment portion of the study by the 
investigator or terminate their participation prematurely based on the following: 
 
• 
Post-consent determination of ineligibility based on safety or eligibility criteria 
• 
Lack of therapeutic efficacy, as evidenced by progression of treated intrahepatic 
(i.e. lack of therapeutic efficacy that will not benefit from additional treatment with 
LC or ONCOZENE beads, loaded with Irinotecan) 
• 
Interval down staging of target lesions such that the subject would be an 
acceptable candidate for curative treatments 
• 
Physician’s judgment following an adverse event 
• 
Termination by the Sponsor or a regulatory authority 
• 
Any other reason for withdrawal that the study physician or subject indicates is in 
the overall best interest of the subject including initiating other oncotherapy 
Subjects who withdraw consent prior to receiving any therapy will be withdrawn from 
the study and no follow-up safety surveillance is required. These will be captured as 
screen fails on the Enrollment Logs. 
 
Subjects who voluntarily withdraw consent or who are withdrawn by the study physician 
for any reason after receiving therapy will be followed up for at least 7 days. The purpose 
of this follow-up is to capture all adverse events and document any serious, procedure 
related adverse events. 
 
If a subject dies prior to the last scheduled study visit, the date and cause of death will be 
recorded. 
 
4.3 
Study Termination 
 
The study will be considered terminated for a subject if: 
 
• 
Consent has been revoked by the subject, or 
• 
Subject has been deemed Lost to Follow-Up, or 
• 
Upon the subject’s death 
 
5 Data Analysis and Statistical Considerations 
 
Fifty-four subjects will be enrolled into the study and randomized to combination therapy or 
systemic therapy in a 1:1 fashion. This section details the sample size calculation and provides 
justification for this number of subjects along with the randomization plan. 
 
 
5.1 
Sample Size Calculation 
 
The primary endpoint will be tumor response, as defined by the modified RECIST criteria.  
Subjects exhibiting complete or partial response will be classified as responders and all 
other subjects as non-responders. The response rate in the intravenous chemotherapy 
group can be assumed to be 25%, and we expect to see response rates of 70% in the 


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chemoembolization with LC and ONCOZENE beads loaded with Irinotecan group. The 
sample size of 54 subjects provides 80% power for a Fisher’s exact test to detect the given 
difference between the assumed proportions at a significance level of 0.05. 
5.2 
Randomization 
 
The 54 subjects will be randomized in a 1:1 ratio to receive either combination therapy or 
systemic therapy alone. A randomized list using an envelope lottery method will be 
generated by the Sponsor. The lottery numbers will be assigned by the Sponsor and 
administered by the Sponsor’s Study Coordinators. She/he will be the only person(s) with 
access to the lottery assignments if the need arises for review. This lottery style envelope 
will be locked and will not be viewed by any of the treating personnel. Subjects will receive 
either combination therapy or systemic therapy alone based on the randomization via the 
sealed opaque envelope method. This is an acceptable way to ensure that subject assignment 
is not predictable and leads to complete randomization. The principal investigator, all 
investigators, as well as other research personnel, will not be aware of the starting point once 
the randomized portion of the study is commenced. 
 
One master envelope containing 54 sealed individual envelopes will be created at the 
beginning of the randomized part of this study and will be randomly given to the study 
coordinator to be opened after a subject has been consented to the study. 
 
5.3 
Populations for Analysis 
 
The As Treated population will include all randomized subjects who receive at least one 
cycle of intravenous chemotherapy or LC or ONCOZENE beads loaded with Irinotecan. 
Subjects will be included in the As Treated Population according to treatment actually 
received. 
 
The Intention-to-treat (ITT) population will include all randomized subjects who receive 
at least one cycle of intravenous chemotherapy or LC or ONCOZENE beads loaded with 
Irinotecan.  All subjects will be grouped according to their randomization regardless of 
treatment received. 
 
The Modified intention-to-treat (MITT) population will include all randomized subjects 
who receive at least one cycle of intravenous chemotherapy (control group) or at least one 
chemoembolization treatment with LC or ONCOZENE beads loaded with Irinotecan (test 
group) and whose progression free survival is evaluable. 
 
The Per-protocol (PP) population will include all subjects who receive at least one 
intravenous chemotherapy cycle (control group) or at least one chemoembolization 
treatment with LC or ONCOZENE beads loaded with Irinotecan in combination with 
intravenous chemotherapy (test group) and who were treated according to their 
randomization schedule. Subjects with major protocol deviations or who did not receive 
treatment according to their randomization schedule will be excluded from the PP 
population. 
 
 
5.3.1 Subject Demographics/Other Baseline Characteristics 
 
The following demographic and baseline characteristics will be summarized 
descriptively by treatment group: 
 
• 
Gender and age 
• 
ECOG performance status 


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• 
Bilobar disease 
• 
Tumor marker (CA19-9) 
• 
Disease status 
• 
Other characteristics (e.g. liver chemistry) 
Medical history will be coded and summarized by primary body system organ class 
and preferred term. 
 
5.3.2 Treatments (study treatments and concomitant medications) 
 
The number and dose of intravenous chemotherapy cycles and the number of 
chemoembolization treatments and dose of LC or ONCOZENE beads, loaded with 
Irinotecan will be summarized by treatment group. 
 
5.4 
Efficacy Analysis 
 
5.4.1 Primary Endpoint 
 
All safety parameters will be analyzed descriptively based on the As Treated 
population and reported in an interim report to FDA The primary objective of the study 
is to test the superiority of transarterial chemoembolization using LC or ONCOZENE 
beads loaded with Irinotecan in combination with first line chemotherapy (test group) 
compared with first line chemotherapy alone (control group) in terms of tumor 
response.  Any subjects that withdraw before study end will be censored at that point. 
 
The hypotheses to be tested for this primary efficacy endpoint are as follows: 
 
• 
H0:  Tumor response under chemotherapy and chemoembolization is the 
same as that under chemotherapy alone (Stest(t) = Scontrol(t)) 
• 
HA:  Tumor response under chemotherapy and chemoembolization is better 
than that under chemotherapy alone (Stest(t) >Scontrol(t)) 
The primary efficacy analysis will be performed on the MITT population. For 
sensitivity reasons, the primary efficacy analysis will also be carried out for both ITT 
and PP populations. 
 
In general, missing data will not be replaced, if not absolutely indicated. 
 
5.4.2 Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints will be the following variables: 
 
• 
Local Tumor Response (extent of necrosis in the treated lesions) 
• 
Time to Progression 
• 
Hepatic Progression Free Survival 
• 
Change in tumor markers 
• 
Overall survival 
• 
Patient Tolerance 
 
Categorical variables will be summarized using frequency tables and Fisher’s exact 
test will be used to compare the treatment groups. Multivariate analyses and logistic 
regression will be applied to adjust the influences of center and other prognostic 
factors, if appropriate. 


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For time-to-event variables, the Kaplan-Meier method will be used to estimate the 
event free survival, and the log-rank test will be conducted to compare the two 
treatment groups. Multivariate analysis and Cox’s proportional hazard model will be 
used to adjust for the influences of center and other prognostic factors, if appropriate. 
For continuous variables, descriptive statistics will be provided and Student’s t tests 
will be used to compare treatment groups.  A linear mixed model will be employed to 
compare the two treatment groups: with treatment, time (if applicable), center and 
other prognostic factors as fixed effects, time-window as a repeated factor (if 
applicable), and subjects as a random factor. 
 
All secondary efficacy analyses will be based on the ITT population and the 
corresponding statistical testing results will be interpreted in the exploratory sense. 
 
6 Ethical and Legal Considerations 
 
6.1 
Informed Consent Procedures 
 
Subject’s informed consent will be obtained and documented according to the principles 
of informed consent in the current version of the 21CFR50 (Protection of Human Subjects), 
Declaration of Helsinki (2008) and the International Conference on Harmonization 
Guideline for Good Clinical Practice (ICH-GCP). 
 
Prior to obtaining informed consent, subjects will be given a full explanation, in lay terms, 
of the study purpose and procedures related to the study. The risks and benefits of the 
procedures will be explained to the subject. The palliative role of chemoembolization 
should be clearly understood by both the subject and his/her family (if appropriate). 
Subjects should also be informed about post-embolization syndrome (PES) that may be 
experienced in over 60% of cases, as well as other treatment-related complications. Post 
embolization syndrome often includes pain, fever, nausea and vomiting that can last from 
a few hours to a few days. Subjects will be informed of the potential risk of treatment 
related death. 
 
It will be explained that they may refuse to take part in, or withdraw from the study without 
prejudice to their future care and treatment. Subjects should not be coerced, persuaded, or 
unduly influenced to participate or remain in the trial. A subject must be given ample time 
and opportunity to inquire about details of the trial and all questions about the trial should 
be answered to the satisfaction of the subject. 
 
Written informed consent will be obtained from all subjects prior to entry into the study. 
The written informed consent document must be IRB-approved and must be signed and 
personally dated by the subject. If the subject is unable to read the consent form, a witness 
should be present during the entire informed consent discussion. The subject will be given 
a copy of his/her signed informed consent document. 
 
 
6.2 
Notification/Submission to Regulatory Authority(ies) 
 
The investigator will assure that an appropriately constituted Institutional Review Board 
(IRB) complies with the requirements of the International Conference on Harmonization 
Guidelines. Prior to initiation of the study, the investigator will forward copies of the 
protocol, informed consent form and all other appendices to be used for the study to the 
IRB for its review and approval. A copy of the approval from the IRB plus other 
regulatory documents must be forwarded to the sponsor or their designee, before any 


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investigational supplies can be shipped to the investigator. 
6.3 
Local Regulations and Declaration of Helsinki 
 
The investigator will ensure that this study is conducted in full conformance with US 
Title 21CFR50 (Protection of Human Subjects), the principles of the “Declaration of 
Helsinki” (as amended in Japan, Italy, Hong Kong, South Africa, Scotland, USA and 
Japan (2008) or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The study must 
fully adhere to all applicable local regulatory requirements, inclusive of US Title 
21CFR812 (Investigational Device Exemptions). 
 
6.4 
Subject Privacy / Confidentiality 
 
All data generated from this study will remain confidential and no published report will 
contain any reference to subject names or identifying features. The investigator will assure 
that subjects protected health information will be securely maintained protected from 
unauthorized parties. 
 
6.5 
Monitoring Procedures 
 
The trial will be monitored to verify that the rights and well-being of subjects are 
protected, that the reported trial data are accurate, complete and verifiable from source 
documents and that the conduct of the study complies with the current approved 
protocol/amendments(s), with Good Clinical Practice, and with the applicable laws 
and/or regulations. 
 
The Sponsor or its designee will be responsible for monitoring the trial according to their 
SOPs, GCP and applicable regulations in order to ensure that investigator recruitment, and 
study initiation, execution and closure are adequate. 
 
It is understood that the responsible monitor (or designee) will contact and visit the 
investigator regularly and will be allowed, on request, to inspect the various records of the 
trial (Case Report Forms and other pertinent data) provided that subject confidentiality is 
maintained in accord with local requirements. As such, the investigator and their staff will 
be expected to cooperate with the Sponsor or its designee and to be available during at 
least a portion of the monitoring visits to answer questions and to provide any missing 
information. 
 
It will be the monitor's responsibility to inspect the Case Report Forms (CRF) at regular 
intervals throughout the study, to verify the adherence to the protocol and the 
completeness, consistency and accuracy of the data being entered on them. The monitor 
should have access to laboratory test reports and other subject records needed to verify 
the entries on the Case Report Form. The investigator (or his/her deputy) agrees to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
 
 
Data monitoring will be conducted by designated monitoring personnel at University of 
Louisville, School of Medicine Department of Surgery. 
 
6.6 
Source Data Verification 
 
Source data verification (SDV) is an essential element to ensure accuracy and credibility 
of the data, and conclusions derived from clinical investigations. Source data verification 
will normally be conducted in conjunction with data monitoring. Entries in the Case 


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Report Forms (CRF) will be verified using the original documents such as subject files, 
informed consent forms signed by subjects, device/drug accountability forms, and hospital 
medical records. 
 
Investigational sites shall supply the Sponsor or its designee on request with any required 
background data from the study documentation or clinic records. This is particularly 
important when Case Report Forms are illegible or when errors in data transcription are 
suspected. In case of special problems and/or governmental queries or requests for audit 
inspections, it is also necessary to have access to the complete study records, provided that 
subject confidentiality is protected. 
 
Investigators and/or Research coordinators at the clinical site will perform primary data 
collection based on source-documented hospital chart reviews.  University of Louisville 
Department of Surgery will provide clinical monitoring on behalf of the Sponsor, 
including review of CRFs and parity checks with the source documentation including 
operator work sheets retained with CRF documentation and hospital charts. 
 
6.7 
Study Quality Assurance 
 
The Sponsor has designated Office of Clinical Research Services and Support (OCRSS – 
the Central Clinical Trials Office at the University of Louisville) to act as the QAU for this 
IDE application. The QAU will provide assurance to the Sponsor that all regulatory 
requirements have been met related to the submission of the IDE and related documents. 
The monitoring of the trial conduct will be handled as discussed in the monitoring section 
above. 
 
 
7 IRB Information 
 
The following IRBs will review and approve the research related to this IDE: 
 
Human Subjects Protection Program  
University of Louisville Institutional Review Board 
Med Center One, Suite 200 
University of Louisville  
501 E. Broadway 
Louisville, Kentucky 40202 
Phone: (502) 852-5188 
Fax: (502) 852-2164 
Chairperson: Laura Clark, MD 
 
8 Investigator Agreements 
 
8.1 
Certification of Investigator Agreement 
 
The sponsor certifies that: 
 
All the investigators who participate in the investigation have signed an Investigator 
Agreement. 
 
The list of investigators provided in the previous section includes all the investigators 
participating in the clinical investigation of the device. 
No investigators will be added to the clinical investigation of the device until they have 
signed an Investigator Agreement. 


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9 Reference List 
 
1. 
Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation 
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Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, 
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Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled 
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LB. A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma. 
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Ducreux M, Van Cutsem E, Van Laethem JL, Gress TM, Jeziorski K, Rougier P, 
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Kim MJ, Oh DY, Lee SH, Kim DW, Im SA, Kim TY, Heo DS, Bang YJ. 
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platinum in unresectable biliary tract cancer: a retrospective study. BMC Cancer 
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14. 
Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, 
Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to 
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15. 
Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, Nematollahi M, Pond GR, 
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Knox JJ, Hedley D, Oza A, Siu LL, Pond GR, Moore MJ. Gemcitabine concurrent 
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Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of 
gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract 
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18. 
Lee GW, Kang JH, Kim HG, Lee JS, Jang JS. Combination chemotherapy with 
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20. 
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21. 
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23. 
Kameyama M, Imaoka S, Fukuda I, Nakamori S, Sasaki Y, Fujita M, Hasegawa Y, 
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24. 
Kato T, Nemoto R, Mori H, Takahashi M, Harada M. Arterial chemoembolization 
with mitomycin C microcapsules in the treatment of primary or secondary carcinoma 
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Kato T, Nemoto R, Mori H, Takahashi M, Tamakawa Y, Harada M. Arterial 
chemoembolization with microencapsulated anticancer drug. An approach to 
selective cancer chemotherapy with sustained effects. JAMA 1981;245:1123-7. 
 
26. 
Fujimoto S, Miyazaki M, Endoh F, Takahashi O, Okui K, Morimoto Y. 
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hepatic cancer. With particular reference to a comparison with continuous infusion of 
mitomycin C and 5-fluorouracil. Cancer 1985;56:2404-10. 
 
27. 
Cantore M, Mambrini A, Fiorentini G, Rabbi C, Zamagni D, Caudana R, Pennucci C, 
Sanguinetti F, Lombardi M, Nicoli N. Phase II study of hepatic intraarterial 
epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable 
biliary tract tumors. Cancer 2005;103:1402-7. 
 
28. 
Kemeny NE, Ron IG. Liver Metastases. Curr Treat Options Gastroenterol 1999;2:49- 
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29. 
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venous flow on the washout of a regionally injected marker substance 99mTc- 
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microspheres. Eur J Surg Oncol 1992;18:347-52. 
 
30. 
Pentecost MJ. Transcatheter treatment of hepatic metastases. AJR Am J Roentgenol 
1993;160:1171-5. 
 
31. 
Geoghegan JG, Scheele J. Treatment of colorectal liver metastases. Br J Surg 
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32. 
Patel NH, Jindal RM. The role of chemoembolization in the treatment of colorectal 
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33. 
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Abramson RG, Rosen MP, Perry LJ, Brophy DP, Raeburn SL, Stuart KE. Cost- 
effectiveness of hepatic arterial chemoembolization for colorectal liver metastases 
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35. 
Urego M, Flickinger JC, Carr BI. Radiotherapy and multimodality management of 
cholangiocarcinoma. Int J Radiat Oncol Biol Phys 1999;44:121-6. 
 
36. 
Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, Gonwa T, 
Klintmalm G. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 
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37. 
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de Forni M, Bugat R, Chabot GG, Culine S, Extra JM, Gouyette A, Madelaine I, 
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patients with colorectal cancer: an interim report. World J Surg Oncol 2009;7:80. 
 
41. 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 
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in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711. 


 
 
 
 
Attachment A - Protocol Schema 
 
Study Schema - Control Subject 
Week Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9† 
LT-FU 
S-FU 
Baseline/ 
Screening 
Active Treatment 
q 3-4 
months‡ 
q 3-4 
months≠ 
Cycle 1 
Cycle 2 
Cycle 3 
Gem-Cis/Gem-Carbo Chemotherapy 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion 
x 
Informed consent 
x 
Demographics 
x 
Medical / Surgical History 
x 
Physical Exam/Nursing Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
      CBC, CMP  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
* 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Tumor markers 
x 
x 
x 
Magnesium 
 
x 
x 
 
x 
x 
 
x 
x 
x 
 
CT chest 
x 
 
 
3 phase CT/MRI abd. and pelvis 
x 
x 
x∞ 
AE Monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x# 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x# 
Telephone / S.O.C. Physician Visits 
x 
*if clinically indicated 
†Additional active treatment in 3 Cycle increments 
‡Upon completion of Active Treatment w/o P.O.D. 
∞If no P.O.D. upon completing 1 year of LT-FU, only radiological FU is continued 
#Followed up to 30 days post last active study treatment 
≠Completed upon evidence of P.O.D. until Death 
 
 
 
 
 
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Page 44 of 48  


 
 
 
 
Study Schema - Treatment Subject 
Week Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10† 
LT-FU 
S-FU 
Baseline 
Screening 
Active Treatment 
q 3-4 
months‡ 
q 3-4 
months≠ 
Cycle 1 
Cycle 2 
Cycle 3 
Chemoembolization 
x 
x 
x* 
Gem-Cis/Gem-Carbo Chemotherapy 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion 
x 
Informed consent 
x 
Demographics 
x 
Medical / Surgical History 
x 
Physical Exam/Nursing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
     CBC, CMP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
* 
* 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Tumor markers 
x 
x 
x 
Magnesium 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
CT chest 
x 
 
 
3 phase CT/MRI abd. and pelvis 
x 
x 
x∞ 
AE Monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x# 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x# 
Telephone / S.O.C. Physician 
Visits
x 
*if clinically indicated 
†Additional active treatment in 3 Cycle increments 
‡Upon completion of Active Treatment w/o P.O.D. 
∞If no P.O.D. upon completing 1 year of LT-FU, only radiological FU is continued 
#Followed up to 30 days post last active study treatment 
≠Completed upon evidence of P.O.D. until Death 
 
 
 
 
 
 
 
 
 
 
 
 
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DELTIC study 
                                    Page 45 of 48 


 
Attachment B 
Study Treatment Plan 
 
 
CONTROL GROUP 
The Control Group will receive Gem/Cis or 
Gem/Carbo chemotherapy at the following time 
points: 
 
 
 
Week 1: Chemo Cycle 1 (Day 1) 
 
Week 2: Chemo Cycle 1 (Day 8) 
 
Week 3: REST 
 
Week 4: Chemo Cycle 2 (Day 1) 
 
Week 5: Chemo Cycle 2 (Day 8) 
 
Week 6: REST 
 
Week 7: Chemo Cycle 3 (Day 1) 
 
Week 8: Chemo Cycle 3 (Day 8) 
 
Week 9: CT or MRI and office visit to evaluate 
response to therapy. This schedule of 
treatments will continue based on 
subject’s tolerance and response to 
therapy. 
 
 
 
 
TEST GROUP 
The Test Group will receive LC or 
ONCOZENE beads chemoembolizations 
and Gem/Cis or Gem/Carbo chemotherapy 
at the following time points: 
 
Week 1: Bead Treatment 
 
Week 2: Chemo Cycle 1 (Day 1) 
 
Week 3: Chemo Cycle 1 (Day 8)  
Week 4: Bead Treatment  
Week 5: Chemo Cycle 2 (Day 1) 
Week 6: Chemo Cycle 2 (Day 8)  
Week 7: Bead Treatment  
Week 8: Chemo Cycle 3 (Day 1) 
Week 9: Chemo Cycle 3 (Day 8) 
 
Week 10: CT or MRI and office visit to 
evaluate response to therapy. This 
schedule of treatments will 
continue based on subject’s 
tolerance and response to therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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R 
A 
N 
D
O
M 
I 
Z 
E 
Attachment C - Study Treatment Plan 
 
 
 
 
 
 
 
CONTROL GROUP 
 
   
 
Standard chemotherapy 
                                                                                                 Gem/Cis or Gem/Carbo q 3 weeks 
 Eligible patients with  
        unresectable 
   intrahepatic cholangiocarcinoma 
 
 
 
                                                                        TREATMENT GROUP                             
                                                                LC or ONCOZENE Beads plus Standard Chemotherapy 
                                                                                   Beads q 3 weeks starting on Week 1  
                                                                           Chemo cycle q 3 weeks starting on Week 2   
                                                                                            
                                            
                                                 
CONTROL GROUP: 
 
Standard chemotherapy consisting of Gemcitabine / Cisplatin or Gemcitabine / Carboplatin*  
 
Each chemotherapy cycle is 21 days consisting of Gem/Cis or Gem/Carbo infusions on Day 1 and 
Gem/Cis or Gem alone on Day 8 and 1 week of rest following. (There is a +/- 3 day window on all 
chemotherapy treatments.) 
 
• 
Cisplatin at 25 mg/m2 given as a 2-hour IV infusion on Days 1 and 8. 
• 
Or, Carboplatin given as a 2-hour IV infusion on Day 1 only.  Carboplatin dose (mg) = (target 
AUC) x (GFR + 25) with a target AUC of 4.The max dose for AUC of 4 is 600 mg. 
• 
And, Gemcitabine at 1000 mg/m2 given as a 30-minute IV infusion after Cisplatin or Carboplatin on 
Day 1 and after Cisplatin on Day 8. 
OR 
TEST GROUP: 
 
Chemoembolization with Irinotecan loaded-LC or ONCOZENE beads plus standard 
chemotherapy consisting of Gemcitabine / Cisplatin or Gemcitabine / Carboplatin.* 
 
• 
Chemoembolization with Irinotecan loaded-LC or ONCOZENE beads performed q 3 
weeks, starting on Week 1** (There is a +/- 3 day window on all chemoembolization 
treatments.) 
 
First chemotherapy treatment will occur one week after the first chemoembolization procedure which 
occurs at Week 2 on the study calendar. Each chemotherapy cycle is 21 days, consisting of Gem/Cis 
or Gem/Carbo infusions on Days 1 and Gem/Cis or Gemzar alone on Days 8 and 1 week of rest 
following.  (There is a +/- 3 day window on all chemotherapy treatments.) 
 
• 
Cisplatin at 25 mg/m2 given as a 2-hour IV infusion on Days 1 and 8, starting on Week 2.** 
• 
Or, Carboplatin given as a 2-hour IV infusion on Day 1 only starting on Week 2.  Carboplatin dose 
(mg) = (target AUC) x (GFR + 25) with a target AUC of 4.  The max dose for AUC of 4 is 600 mg. 
• 
And, Gemcitabine at 1000 mg/m2 given as a 30-minute IV infusion after Cisplatin or Carboplatin on 
Day 1 and after Cisplatin on Day 8. 
 


 
 
*All treatment regimens will be given until progression of disease or until the treating physician 
determines it is in subject’s best interest to discontinue therapy. 
 
**Subjects in the TEST GROUP may receive additional chemoembolization treatments, up to a 
maximum number of 6 treatments, if the investigator believes this in subject’s best interest, based on 
subject’s response and tolerance to treatment and subject’s overall burden of disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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