Phase II Study of Drug-eluting Irinotecan Beads (DEBIRI) in Refractory Metastatic Colorectal Cancer With Liver-only or Liver-predominant Disease
Phase: PHASE1
Conditions: Liver Metastases, Mucinous Adenocarcinoma of the Colon, Mucinous Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Signet Ring Adenocarcinoma of the Colon, Signet Ring Adenocarcinoma of the Rectum, Stage IV Colon Cancer, Stage IV Rectal Cancer
Sponsor: Fox Chase Cancer Center

GI-063 
 
 
 
 
GI-063 Phase I Study Of Drug-Eluting Irinotecan Beads (Debiri) In Refractory Metastatic 
Colorectal Cancer With Liver-Only Or Liver-Predominant Disease. 
 
IDE Number:  G100031/S009 
 
 
 
Principal Investigator 
Efrat Dotan, M.D. 
Fox Chase Cancer Center  
333 Cottman Avenue 
Philadelphia, PA 19111 
Tel: 215-728-2450 
Fax: 215-214-3229 
Email: Efrat.dotan@fccc.edu 
 
Co-Investigator  
Gary Cohen, M.D. 
Temple University 
3401 North Broad Street  
Philadelphia, PA 19140 
Tel: (215) 707-4723  
Fax: (215) 707-2428 
Email: Gary.Cohen@tuhs.temple.edu 
 
 
Statistician 
Karthik Devarajan, Ph.D.  
Fox Chase Cancer Center  
333 Cottman Avenue 
Philadelphia, PA 19111 
Tel: 215-728-2794 
Fax: 215-728-2553 
Email: Karthik.Devarajan@fccc.edu 
 
Sub-Investigators 
Juhi Mittal, MD 
 
Joseph Panaro, MD 
 
Mark Burshteyn, MD 
 
Emily Cuthbertson, MD 
 
David Pryluck, MD 
 
Dmitry Niman, MD 
  
 
 
 
 
 
 
 
 
Version Date:  November 29, 2013 
Amendment  1:  October 9, 2015 
Amendment 2: February 27, 2017 

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Schema 
 
Dose Escalation Schedule 
Dose Level 
Dose of Irinotecan 
Level 1 
50 mg per dose 
Level 2 
75 mg per dose 
Level 3 
100 mg per dose 
Each patient will be treated with a maximum of two treatments per affected lobe.  
Cohort will be expanded at the Maximum Tolerated Dose. 
The below Schema will be followed at each dose level. 
 
Refractory metastatic colorectal cancer patients with liver only or liver predominant 
disease. 
 
 
 
 
 

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Contents 
1.0 Introduction ...................................................................................................................5 
1.1 Colorectal cancer – systemic therapy .............................................................................5 
1.2 Rationale for intrahepatic therapy in colorectal cancer ...................................................5 
1.3 Drug Eluting Irinotecan Beads (DEBIRI) – preliminary data: ........................................6 
1.4 Drug Eluting Irinotecan Beads (DEBIRI) – previous experience: ...................................8 
1.5 The Agent – Irinotecan: .................................................................................................9 
2.0 
Objectives .................................................................................................................9 
2.1 
Primary Objectives ....................................................................................................9 
2.2 
Secondary Objectives ................................................................................................9 
3.0 
Patient selection .........................................................................................................9 
3.2 
Exclusion ................................................................................................................ 11 
3.3 
Pregnancy ................................................................................................................ 12 
3.4 
Patient withdrawal ..................................................... Error! Bookmark not defined. 
3.5 
Patient Registration ................................................................................................. 12 
4.0 Treatment plan ............................................................................................................. 12 
4.1 
DEBIRI dose: .......................................................................................................... 13 
4.1.1 Patients with unilobar disease .................................................................................... 13 
4.1.2 Patients with bi-lobar disease .................................................................................... 13 
4.2 
Technique for delivering DEBIRI ............................................................................ 14 
4.3 
Definition of Dose-Limiting Toxicities .................................................................... 15 
4.4 
Supportive care guidelines ....................................................................................... 17 
4.5 
Duration of therapy .................................................................................................. 17 
4.6 
Concomitant medications ........................................... Error! Bookmark not defined. 
4.7 
Follow Up ............................................................................................................... 17 
5.0 
Adverse Events ........................................................................................................ 18 
5.1 
Definitions ............................................................................................................... 18 
5.2 Recording and Reporting Responsibilities ................................................................................... 19 
6.0 DEBIRI formulation and procurement .......................................................................... 21 
7.0 Study Calendar ............................................................................................................ 22 
Definitions ......................................................................................................................... 24 

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8.1 
Response Criteria ..................................................................................................... 24 
8.2 
Duration of response ................................................................................................ 25 
8.3 
Time to progression ................................................................................................. 26 
9.0 
Statistical Considerations: ........................................................................................ 26 
9.2 
Data Safety Monitoring Plan .................................................................................... 26 
9.2.1  Monitoring Plan........................................................................................................................ 27 
9.2.2 Data Safety Monitoring Committee .......................................................................................... 27 
10.0 Administrative ........................................................................................................... 27 
10.1 Data Reporting ........................................................................................................................... 27 
10.2 Retention of Records .................................................................................................................. 27 
10.3 Study Agents .............................................................................................................................. 28 
10.4 Informed Consent ....................................................................................................................... 28 
Appendix A – Pre-treatment orders: ................................................................................... 29 
Appendix B– Post-treatment order form:............................................................................ 30 
Appendix C - DEBIRI adverse event profile ...................................................................... 31 
References: ........................................................................................................................ 36 
 
 
 
 

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1.0 Introduction 
 
Liver metastases secondary to colorectal cancer continue to pose a therapeutic challenge for oncologists. 
Since the liver is the most common site of metastatic disease in colorectal cancer, it is reasonable to consider 
local therapy in these circumstances. Surgical resection of liver metastases has been proven to prolong 
survival in patients with colorectal cancer (1). Several studies have been conducted to study the role of 
various intra-hepatic therapies for these tumors. In recent years, irinotecan drug eluting beads (DEBIRI) 
have been introduced to the market for local therapy of liver metastases from colorectal cancer. The dose 
used in practice has not been subjected to a formal evaluation for identification of the maximum tolerated 
dose. Therefore, we propose a phase I study to determine the maximum tolerated dose of drug eluting 
irinotecan beads for local treatment of refractory colorectal liver metastases. 
 
 
1.1 Colorectal cancer – systemic therapy 
 
Colorectal cancer is the second leading cause of cancer death in the United States, with nearly 150,000 
cases yearly (2). For many years, standard therapy for advanced colorectal cancer consisted of 5-
fluorouracil (5-FU) modulated by leucovorin (LV), with antitumor response rates of 15-20% and median 
survival of approximately one year (3). Recently, the addition of either irinotecan or oxaliplatin to 
fluoropyrimidine therapy has resulted in improved response rates of 40-50%, with median survival exceeding 
18 months. Single agent irinotecan treatment in 5-FU refractory patients was found to be effective with 
reported response rates of about 10% (4, 5). Therapies targeting the vascular endothelial growth factor and 
epidermal growth factor receptor (EGFR) further improve outcome (6-10). 
 
Despite progress with systemic therapy, the vast majority of patients with metastatic colorectal cancer 
(mCRC) will die from disease. The liver is the most common site of metastatic spread for colorectal 
cancer. Studies have shown that resection of liver metastases from colorectal cancer can be curative (11). 
Unfortunately, only a small fraction of patients with metastases confined to the liver are able to undergo 
curative surgery. Thus, there is significant interest in the development of liver-directed therapies, which could 
potentially spare the patient toxicities associated with systemic treatment, and improve their survival. 
Intrahepatic therapy takes advantage of the dual blood supply of the liver. While most normal liver receives 
blood flow from the portal venous circulation, malignant liver tumors receive the majority of their blood 
supply from the hepatic artery (12). 
 
 
 1.2 Rationale for intrahepatic therapy in colorectal cancer 
 
An expanding body of literature is available supporting the use of liver-directed therapy in metastatic 
colorectal cancer. Several investigations of intra-hepatic chemotherapy in colorectal cancer have been 
undertaken, with the most frequently utilized agent being 5- fluoro-2'-deoxyuridine (FUDR). A meta-
analysis comparing systemic to intra-hepatic chemotherapy concluded that intra-hepatic therapy improves the 
antitumor response rate in liver (13). However, when trials containing only fluoropyrimidine in both arms 
were assessed, no impact on overall survival was demonstrated.  More recently, a randomized study 
comparing intra-hepatic FUDR to systemic therapy in patients with metastatic colorectal cancer confined 
to liver demonstrated a small but significant survival benefit of FUDR over systemic 5-FU alone (14). 
Expanding experience with intra-hepatic FUDR suggests that it can be administered safely with systemic 
irinotecan or oxaliplatin (15-18). However, intra-hepatic chemotherapy requires surgical placement of an 
infusion pump, which limits its widespread adoption and applicability. Furthermore, small but clinically 
meaningful subgroups of patients suffer irreversible biliary injury with FUDR therapy. 
 
Other techniques for localized therapy including radiofrequency ablation, stereotactic radiosurgery, 
cryotherapy and arterial chemoembolization have been attempted with various results and less toxicity than 

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intrahepatic chemotherapy (19). Trans-arterial chemoembolization (TACE) has gained renewed interest in 
recent years. This technique consists of delivery of high concentrations of chemotherapeutic agents to the 
tumor bed followed by embolization. The embolization is performed to induce oxygen and nutrient depletion 
to the tumor while minimizing the chemotherapy wash-out. Using this method the extent of systemic toxicity 
is reduced significantly. This approach has been studied in mCRC with reports of up to 50% response rates       
(20-27). 
 
 
 1.3 Drug Eluting Irinotecan Beads (DEBIRI) – preliminary data: 
 
Preliminary studies have evaluated the use of drug-eluting chemotherapy beads (DEB) for localized 
treatment of hepatocellular carcinoma (HCC) and colorectal  liver metastases. These beads are not intended to 
occlude the vessel, but rather locally deliver cytotoxic therapy, resulting in increased intra-tumoral drug 
concentrations with decreased systemic exposure (19). The use of drug-eluting beads can provide a 
higher concentration of irinotecan in the liver without the need of a surgically implanted delivery pump and 
can be an outpatient procedure. These beads obviate the need for an oil/chemotherapy suspension, thus 
facilitating the handling and delivery and achieving TACE in a simpler one-step procedure (28, 29). 
 
The concept of DEB was initially introduced in patients with HCC using doxorubicin DEB (30). Varela et 
al evaluated the use of TACE with doxorubicin DEB in 27 patients with HCC and Child score A (31). The 
procedure was well tolerated, with high response rates of 75%, and 2 year survival rates of 88.9%. Similar 
results were seen by Malagari et al in patients with unresectable HCC and Child score A or B, with about an 
80% response rate and good tolerance to the procedure (32, 33). The use of doxorubicin DEB was also tested 
following radiofrequency ablation of a solitary unresectable HCC (34). In 12 of 20 treated patients (60%), 
complete response was seen following treatment with doxorubicin DEB. Lammer et al thus conducted a 
randomized phase II study of 212 patients with Child-Pugh A or B cirrhosis and unresectable HCC, 
comparing doxorubicin DEB with conventional chemoembolization with doxorubicin. Objective responses 
were higher in the doxorubicin DEB arm compared to conventional TACE (52% versus 44% 
respectively), with marked decrease in toxicity (35). A separate group reported improvement in overall 
survival among patients with unresectable HCC and Child-Pugh A or B treated with doxorubicin DEB 
compared to conventional TACE (36). Van Malenstein et al randomly assigned 30 patients to receive 
either doxorubicin DEB or TACE. The study showed DEB led to lower plasma levels of the cytotoxic 
drug and minimized toxicity while having a comparable tumor response (37). Song et al compared 60 HCC 
patients who underwent TACE with DEB to 69 patients who received conventional TACE. The results 
showed that patients given the DEB treatment resulted in a significantly improved treatment response and 
longer time to progression while having comparable liver toxicity (38).  
 
Irinotecan drug-eluting beads (DEBIRI) were tested in vitro and in rat models with colorectal cancer 
liver metastases and were found to be have anti-tumor activity, with a favorable safety profile (39, 40). 
Preclinical histopathology studies revealed that with DEBIRI results in a predicted necrotizing 
vasculopathy in the arteries/arterioles containing beads, and a granulomatous inflammatory reaction around 
the beads which is typical of embolization without significant hepatocellular damage (29). A feasibility 
study by Aliberti et al using DEBIRI in 10 patients with liver metastases from colon cancer utilized a 
dose of 100 mg every 3 weeks and found this treatment to be well tolerated (41). The study found a 
significant reduction in CEA level and lesion enhancement in imaging 30 days following the treatment. 
Side effects included right upper quadrant/right shoulder pain requiring analgesics, vomiting, and 
alopecia (41). Similar results were presented by Martin and colleagues using DEBIRI on 55 patients with 
refractory metastatic colorectal cancer (42). 
 
A preliminary clinical trial evaluating treatment with DEBIRI in the setting of metastatic colorectal cancer to 
the liver found high response rates (~80%), reduction in lesion contrast enhancement on imaging and 
acceptable toxicity (43). Prophylactic therapy with antibiotics, anti-emetics, dexamethasone and intravenous 

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hydration was recommended to improve the tolerance of the procedure. A phase II study of DEBIRI in 82 
patients with refractory mCRC confirmed an approximately 80% response rate (44). The majority of patients 
experienced self-limited tolerable nausea, fever, and abdominal pain. 
 
A multi-institutional Phase III study randomized 74 patients with hepatic metastases from colorectal cancer to 
receive DEBIRI versus systemic FOLFIRI The difference was statistically significant, median survival was 
22 months for DEBIRI and 15 months for FOLFIRI. Progression free survival was also significantly better 
for DEBIRI (7 months versus 4 months) as was median duration of improvement in quality of life (8 
months versus 3 months in the FOLFIRI group (45). The DEBIRI group reported a manageable adverse 
event profile for the DEBIRI therapy. The most common grade 2-3 toxicities seen with DEBIRI were: 
abdominal pain – 30%, vomiting- 25% and asthenia- 20%. The investigators followed the changes in liver 
function tests following therapy: 58% of patients had elevation of liver function tests to values greater than 
3 times the upper limit of normal. In addition 18% had elevation of bilirubin. All values normalized after 
3 weeks in time for the next scheduled therapy. There were no dose reductions or treatment delays among the 
patients receiving DEBIRI. 
 
The group led by Martin recently published both registry data and a prospective, multicenter, single-arm 
study administrating DEBIRI as liver directed therapy for metastatic colorectal patients (46-48). The group 
published their efficacy results of 55 patients with previously treated mCRC to the liver who received a 
total of 99 DEBIRI treatments (47). The overall 3 month response rate was 65% with 12% of patients having 
complete response and 53% showing partial response. These outcomes where durable since at 12 month 
follow up 15% of the patients demonstrated complete response, 25% partial response and 42% stable 
disease. Overall median progression free survival was 11 months, with a hepatic specific progression free 
survival of 15 months. The overall survival seen in this heavily pre-treated cohort was 19 months. 
 
Tolerability of DEBIRI was reported in a large cohort of 109 patients treated for various hepatic 
malignancies, of which 76% had metastatic colorectal cancer (48). Patients in this cohort were treated with a 
median dose of 100 mg of irinotecan (range 100-200 mg) to a single lobe and a median number of 
treatments of 2 (range 1-5). Patients with bilobar disease received treatment every two weeks alternating 
between affected lobes. Adverse events occurred in 20% of patients and were mostly grade 2. Post-
embolic syndrome including nausea, vomiting and abdominal pain was the most frequent adverse event 
documented. Additional common adverse events included hypertension, gastritis, dehydration, anorexia 
and anemia. 
 
Of 109 patients, four deaths were judged as at least possibly related to treatment (two from 
gastrointestinal bleeding and two from hepatic dysfunction). Through a multivariate analysis the authors 
identified 4 factors that could predict for development of adverse events: (1) Lack of use of hepatic 
arterial lidocaine; (2) >3 treatments; (3) Stasis; (4) >100mg in 1 treatment dose; and (5) bilirubin >2.0 
with >50% liver involvement (48). The authors concluded that DEBIRI can be safely used to treat carefully 
selected patients with metastatic liver disease. 
 
Given efficacy in refractory disease, Martin et al reported the safety, efficacy and tolerability profile of 
DEBIRI in combination with systemic FOLFOX in the treatment of 10 chemotherapy naïve patients with 
unresectable hepatic metastases from colorectal cancer. All 10 patients received at least 12 cycles of 
FOLFOX and 2 treatments with DEBIRI. The initial 9 and 12 month response rates were 100% (2 CR, 8 
PR). Four (40%) patients could eventually undergo resection and/or ablation and had median overall survival 
of 15.2 months. Only 1 severe procedure related adverse event was reported – a grade 3 hypertensive episode 
requiring overnight hospital observation. DEBIRI was overall well tolerated (49). 
 
 
 

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1.4 Drug Eluting Irinotecan Beads (DEBIRI) – previous experience at Fox Chase Cancer 
Center: 
 
Given the encouraging results at select centers, we initiated a phase II study to evaluate the role of DEBIRI 
for local treatment of refractory colorectal cancer with liver only or liver predominant metastatic disease. 
Four patients were enrolled on the study in 2011 and treated with intra-hepatic DEBIRI at 100 mg per 
treatment. Patients received DEBIRI treatment every 3 weeks. Three of the four patients experienced grade 3 
elevation of alkaline phosphatase consistent with the protocol defined dose limiting toxicity and requiring 
premature closure of the study by the data safety monitoring committee. One of four patients had stable 
disease in the treated lobe after two treatments. The patient’s untreated lobe progressed and he remained on 
study to receive treatment to that site. The patient’s staging scan after two additional treatments showed 
progressive disease and he was taken of study. Table 1 summarizes the outcomes of these patients. 
 
Table 1: FCCC previous experience with DEBIRI: 
Patient # 
Alk Phos 
level pre- 
treatment 
Timing of 
grade 3 
Alk Phos 
elevation 
Outcome 
following Alk 
Phos elevation 
Number of 
treatments 
Overall response 
1 
144 
- 
- 
2 to each 
lobe, 4 
total 
treatments 
SD – right lobe 
PD- left lobe 
2 
137 
DAY 64 
ERCP & STENT 
2 
PD 
3 
225 
DAY 14 
DIED FROM 
PD 
1 
PD 
4 
473 
DAY 1 
PD 
1 
PD 
Alk phos- Alkaline phosphatase; PD- Progressive disease; ERCP- Endoscopic retrograde cholangiopancreatography; 
 
Transient elevation of liver function tests is commonly seen following liver directed therapy. In an 
early study of chemoembolization among patients with hepatocellular carcinoma, these transient changes 
were seen in all treated patients (1). These adverse events were also documented in the Precision V study 
comparing DC beads and TACE for hepatocellular carcinoma. Liver function tests on average doubled 
following DC bead therapy and more than tripled after TACE treatment. As described above, the recent 
phase III study by Fiorentini et al comparing DEBIRI with systemic FOLFIRI reported transient elevation 
of liver function tests in 58% of DEBIRI treated patients (45). With these data in mind, liver function test 
increases are commonly noted in the few weeks immediately following this procedure but they are nearly 
always transient and rarely indicative of significant irreversible liver injury. 
 
It is possible that the alkaline phosphatase elevation noted in our phase II experience was related to this post 
procedural effect. The three patients who had significant elevation were ultimately found to have 
progressive disease on imaging which may have further contributed to this abnormality. 
 
There is a growing body of evidence describing the benefit from DEBIRI use among patients with CRC 
liver metastases. Furthermore, this treatment approach is commonly used in clinical practice despite the 
limited data in the literature. Our phase II experience, however, raises a concern for tolerability of this 
regimen among heavily pre-treated metastatic colorectal patients. There is also lack of data regarding the 
maximum tolerated dose (MTD) of DEBIRI among this patient population and the toxicity profile and 
significance of liver function tests abnormalities among these patients are not known. We therefore propose 
this phase I study to evaluate the tolerability and safety of DEBIRI among patients with refractory 
metastatic colorectal cancer. In this study, in addition to escalating the dose of irinotecan, we will be using 

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a smaller size bead in an attempt to improve tolerability. In lieu of the experience of Martin et al., we 
will limit study treatment to two doses per lobe. 
 
1.5 The Agent – Irinotecan: 
 
Irinotecan is a well-known drug widely used as a systemic chemotherapeutic agent in gastro-intestinal 
malignancies. It is a derivative of the topoisomerase – 1 inhibitor class and exerts its cytotoxic effect by 
binding to topoisomerase – 1 DNA complex and inhibiting DNA repair [49]. It is approximately 50% 
protein bound in the circulation, undergoes non – cytochrome P450 hepatic metabolism and is excreted 
mainly via the biliary route and 20% renally. It has an elimination half-life of 6 to 12 hours. Common 
major side effects seen are nausea, vomiting, diarrhea, loss of appetite, myelosuppression, worsening hepatic 
function and hair loss. 
 
Limited data are available regarding the pharmacokinetics of DEBIRI. Previous studies have shown a 
better toxicity profile compared to systemic irinotecan, with the main adverse event of post embolization 
syndrome (45). Recent data from Martin et al. reported some pharmcokinetics of the drug showing only 
minimally detectable levels of plasma irinotecan and its active metabolite SN-38 after up to 3 DEBIRI 
treatments in chemotherapy naïve patients with hepatic metastases from colorectal cancer. Each DEBIRI 
treatment involved administration of 100mg irinotecan loaded onto 100-300 μm beads and delivered via the 
hepatic artery (49). Our previous experience demonstrated increased alkaline phosphatase with use of the 
100mg dose of DEBIRI among heavily treated patients. It is possible that this patient population is less 
amenable to intrahepatic therapy. Alternatively the use of larger bead size may contribute to the poor 
tolerance. Since refractory patients are often referred for these treatments due to limited treatment options, it 
is important to identify the MTD for this drug in this patient population. In the proposed phase I study we will 
use a smaller bead size and carefully escalate the irinotecan dose. These smaller beads are thought to result in 
better tumor penetration and drug delivery with less embolic effect. We will initiate treatment at 50mg of 
DEBIRI and escalate by 25mg with every subsequent treatment cohort until the MTD is reached. Cohort 
expansion will be planned at the MTD. Data from this trial will be used for development of future 
clinical trials utilizing DEBIRI among patients with refractory disease. 
 
2.0 Objectives 
 
 
2.1 Primary Objectives 
 
To determine the maximum tolerated dose of drug eluting irinotecan beads, delivered intrahepatically for 
the treatment of liver only or liver-predominantly colorectal metastatic disease. 
 
 
2.2 Secondary Objectives 
 
To determine the response rate of colorectal liver metastases treated with drug- eluting irinotecan beads in 
refractory metastatic colorectal patients with liver only or liver predominant disease. 
 
1. To determine the time to progression of colorectal liver metastases treated with drug-eluting 
irinotecan beads in refractory metastatic colorectal patients with liver only or liver predominant disease. 
 
2. To determine the overall survival of patients treated with drug-eluting irinotecan beads for liver only or 
liver predominant metastatic disease from colorectal cancer. 
 
3.0 Patient selection 
3.1 Inclusion 
 

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3.1.1 Patients must be 18 years or older. 
 
3.1.2 Patients must have a histologically or cytologically confirmed adenocarcinoma of the colon 
or rectum that is metastatic to the liver and unresectable and for which standard curative 
measures do not exist or are no longer effective. 
 
3.1.3 Patients must have received prior fluoropyrimidine, oxaliplatin and irinotecan-based therapy 
for their disease and had progression or intolerance to these agents that resulted in treatment 
discontinuation. 
 
3.1.4 Liver disease must not be amenable to potentially curative surgical resection. 
 
3.1.5 Patients must have liver-only or liver-predominant disease to be eligible for this study. Liver 
predominant disease is defined dominant metastatic burden in the liver, with extra-hepatic 
disease that is judged by the investigator as unlikely to be life threatening within 3 months. 
 
3.1.6 Patients must have a patent portal vein as documented by CT, MRI, or ultrasound. 
 
3.1.7 Prior radiation therapy is allowed but must have been completed ≥4 weeks prior to study 
entry. Patients with history of prior radiation to the liver including radio-labeled microspheres 
cannot take part in this study. 
 
3.1.8 Eastern Cooperative Oncology Group performance status 0 or 1. 
 
3.1.9 Previous surgery or RFA to the liver is allowed. Patients with history of 
chemoembolization or radio-labeled microspheres are excluded. 
 
3.1.10 Life expectancy of ≥12 weeks. 
 
3.1.11 Patients must have organ and marrow function as defined below: 
Leukocytes 
≥ 3,000/μL 
Absolute Neutrophil Count 
≥1,500/μL 
Platelets 
≥ 100,000/μL 
Total Bilirubin 
≤1.5X ULN 
AST(SGOT)/ALT(SGPT) 
≤2 X ULN 
Alkaline Phosphatase 
≤2 X ULN 
Creatinine 
≤2.0 X mg/dL 
PT/PTT 
≤1.5 X ULN 
 
3.1.12 Chemotherapy is harmful to the human fetus. For this reason, women of childbearing 
potential (WOCBP) and sexually active males must agree to use an accepted and effective 
method of contraception prior to study entry and for the duration of the study. WOCBP 
include any female who has experienced menarche and who has not undergone successful 
surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is 
not postmenopausal. Women who use oral, implanted or injectable contraceptive hormones, 
or mechanical products such as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g., vasectomy) should be considered to be of child bearing potential. 
 
3.1.13 Patients must demonstrate ability to understand and the willingness to sign a written informed 

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consent document. 
 
3.1.14 Patients must discontinue any medication that causes strong CYP3A4 induction 2 weeks 
prior to treatment initiation. Patients who are not able to discontinue these drugs are considered 
ineligible. 
 
3.1.15 Patients must discontinue any  medication  that  causes  a  strong  CYP3A4 inhibition 1  week  
prior  to  treatment  initiation.  Patient who are not able to discontinue these drugs are 
considered ineligible. 
 
3.2 Exclusion 
 
3.2.1 Patients who have had chemotherapy (including targeted therapy i.e. cetuximab, panitumumab) or 
radiotherapy ≤ 4 weeks or treatment with bevacizumab ≤6 weeks prior to entering the study 
or those who have not recovered from acute adverse events due to agents administered more 
than 4 weeks earlier, with the exclusion of alopecia or neuropathy. Patients with history of 
radiation to the liver including radio-labeled microspheres at any point in their past will be 
excluded. 
 
3.2.2 Patients may not be receiving nor have received any other investigational agent ≤ 4 weeks prior to 
study registration. 
 
3.2.3 Pregnant or nursing women may not participate in this trial because of the increased risk of 
fetal harm including death from the therapeutic agents. 
 
3.2.4 Patients with known brain metastases are excluded from this study because of their poor prognosis 
and frequent development of progressive neurological dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.2.5 Any patients with immune deficiency are at increased risk of lethal infections when treated with 
marrow-suppressive therapy, known HIV-positive patients and those with known hepatitis B or C 
are excluded from the study. 
 
3.2.6 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active 
bacterial infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.7 Patients with clinically evident ascites requiring medical management or paracentesis, or Childs-
Pugh score B/C are not eligible. 
 
3.2.8 Patients with evidence of other cancer within 5 years, excluding adequately treated basal cell 
carcinoma or squamous cell carcinoma of the skin. 
 
3.2.9 Patient with significant cardiac, renal or hematologic or pulmonary dysfunction. 
 
3.2.10 Patients with previous chemoembolization to liver metastases. 
 
 
 

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3.3 Pregnancy 
 
The effects of DEBIRI on the developing human fetus at the recommended therapeutic dose are unknown.  
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of treatment, and for at least 3 
months after the completion of treatment. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she must inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy.  In additional, men enrolled on this 
study should understand the risks to any sexual partner of childbearing potential. 
 
All WOCBP must have a negative pregnancy test within 72 hours prior to receiving the first dose of the 
investigational agent(s).  If the pregnancy test is positive, the patient must not receive protocol treatment and 
must not be enrolled in the study. 
 
WOCBP is defined as follows: Any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a bilateral oophorectomy) or is not 
postmenopausal (defined as amenorrhea > 12 consecutive months, or women on hormone replacement therapy 
(HRT) with documented plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml).  Even women who 
are using oral, implanted, or injectable contraceptive hormones or mechanical products (diaphragm, condoms, 
spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should 
be considered to be WOCBP. 
 
 
3.4 Patient Registration 
 
Eligible participants will be entered on study centrally by the Fox Chase Cancer Center QA Coordinator or 
their designee.  Following registration, participants must begin protocol treatment within 14 days of 
registration.  Issues that would cause treatment delays must be discussed with the Principal Investigator.  If a 
participant does not receive protocol therapy following registration, the participant will be recorded as 
withdrawn from study.  The Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. 
 
Participants may be registered from 9:00 am to 5:00 pm excluding holidays by calling the QA Coordinator at 
215-728-4770.  The site’s investigator or designee will then fax or email the completed registration form, 
consent and HIPAA signature pages and eligibility checklist to 215-214-1511.  The QA Coordinator or 
designee will notify the site by email once registration is confirmed and the sequence number has been 
assigned.  Participants must be registered and have received a sequence number assigned by the QA 
Coordinator prior to the initiation of treatment.   
 
4.0 Treatment plan 
 
This will be a single-center phase I study of DEBIRI for the treatment of metastatic colorectal cancer 
with liver only or liver predominant metastases. Treatment will be given in the interventional radiology 
department. All patients will be hospitalized for observation following DEBIRI treatment. Reported adverse 
events and potential risks of these agents and appropriate dose modifications are described in Section 5.0. No 
investigational or commercial agents or therapies other than those described below may be administered 
with the intent to treat the patient’s malignancy. 
 
The following criteria for recovery of all toxicities must be documented prior to any additional DEBIRI 
treatments. 

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 
Non-hematologic toxicities related to prior DEBIRI therapy must recover to ≤ grade 1 prior to any 
additional treatment. 
 
Alkaline phosphatase/ AST/ALT level must recover to ≤ grade 1 (less than 2.5 the upper limit of 
normal). 
 
Bilirubin elevation must recover to ≤ grade 1 (less than 1.5 the upper limit of normal) 
 
Neutropenia  and  thrombocytopenia  must  recover  to  ≤  grade  1  prior  to  any additional treatment 
 
 
4.1 DEBIRI dose: 
This will be a typical phase I study design of 3+3. The first cohort of patients will receive a dose of 50 mg of 
irinotecan per DEBIRI treatment. We will escalate by 25 mg with subsequent cohorts up to a dose of 100 mg of 
irinotecan per DEBIRI treatment (section 4.3). 
 
 
Table 2: Dose Escalation Schedule 
Dose Level 
Dose of Irinotecan in beads 
Level 1 
50 mg per dose 
Level 2 
75 mg per dose 
Level 3 
100 mg per dose 
 
At each dose level patients will be treated based on the presence of unilobar or bilobar disease and treated 
as described below. 
 
4.1.1 Patients with unilobar disease 
At each dose level the involved lobe will be treated twice with the appropriate dose of DEBIRI once every 
3 weeks. CT scan for evaluation of response will be performed at 8 weeks.  Further treatment is at the 
discretion of the treating physician. 
 
4.1.2 Patients with bi-lobar disease 
At each dose level the dominant lobe will be treated with the appropriate dose of DEBIRI for two treatments 3 
weeks apart. CT images of the liver will be used to determine which lobe has the highest number or the 
largest lesions, and will be considered the dominant lobe. The response will be evaluated with CT at 8 
weeks. In the absence of evidence of progression in the treated lobe (dominant lobe), 2 additional 
treatments can be administered to the untreated (non-dominant) lobe, at the same dose level. Repeat CT 
scan will be performed at 16 weeks. Further treatment is at the discretion of the treating physician. 
 
 
Treatment considerations 
 
 
Prior to each subsequent therapy patients will have all their blood work reviewed, to assure that they 
fill the eligibility criteria set forth for the study in section 3.1.11. 
 
 
Treatment may be delayed up to 2 additional weeks for labs to recover 
 
 
Failure to recover after 2 additional weeks will result in patient removal from the study 
 
 
Evaluating Response 
 
 
For purposes of planning follow-up treatments and measuring response, response will be defined by 
RECIST criteria for the treated lobe only. 

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 
Progression of extra-hepatic metastases or progression in the untreated lobe will not be considered 
progression for the purposes of this trial. However, in these cases the patient and his treating 
physician may elect to terminate participation in this study.  
 
 
Response rate in treated liver lesion will be classified using RECIST criteria as outlined in section 
8.0. 
 
4.2 Technique for delivering DEBIRI 
 
The following procedures will be followed for each treatment: 
 
Pre-treatment: The patient should be kept NPO overnight prior to the treatment. Patients will be adequately 
pre-medicated as per the treating physician recommendation. In addition they will receive hydration, 
analgesics, antiemetics and prophylactic antibiotic therapy at the discretion of the physician performing 
the procedure. Diabetic patients on treatment with drugs from the Biguanides family (i.e. Metformin) will 
be required to discontinue their drug 24hr prior to the procedure and 2 days following the procedure. 
Diabetic patients and patients with creatinine 1.5-2.0 will receive aggressive hydration prior to the 
DEBIRI procedure. (See pre-admission order appendix A) 
 
Pain Management: In prior studies of chemoembolization with LC Bead loaded with irinotecan, all patients 
reported moderate post procedural pain. Post procedure pain should be treated with parenteral narcotics 
under the discretion of the treating physician. Intra-arterial lidocaine (2-4cc) prior to injection of loaded 
beads may be used. 
 
Chemoembolization with DEBIRI equipment: Patients  will receive chemoembolization using LC Bead 
loaded with irinotecan. The beads used in this study will be the smallest size of 70-150µm (nominal). The 
beads will be mixed with a non-ionic contrast media in the vial immediately prior to use according to the 
instructions for use. Irinotecan will be loaded onto the beads not more than 2 hours prior to the procedure. 
The minimal incubation time is 2 hours for 98% absorption, but may be up to 5 hours for 100% 
absorption. Standard loading techniques and incubation time recommended by the sponsor will be used for all 
dose levels to ensure complete loading of the drug onto the beads (outlined in section 6.0). The study goal will 
be to deliver the full dose of irinotecan per treatment at each dose level. However, inherent factors such as 
arterial anatomy or other limiting procedural factors the dose may limit the total dose administered. Stasis 
in the target vascular bed is to be avoided, even if it means not delivering the entire intended dose. 
 
Catheter Compatibility: The following catheter or an equivalent or larger French size catheter is compatible 
with the DEBIRI use. 
 
Trade Name 
Manufacturer 
Size 
ProgreatTM 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. 
 
Procedure: 
Using a unilateral femoral approach, selective catheterization of the hepatic artery will be performed. 
Vascular access is obtained via the common femoral artery and a guide-wire advanced under fluoroscopic 

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guidance. A micro- 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 antegrade portal vein flow. 
The celiac axis is then selected and an angiogram completed. The catheter and guide-wire 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 is 
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 DEBIRI. Patients 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. 
 
Once the catheter is in place within the artery feeding the tumor, the LC Bead, loaded with irinotecan will be 
delivered into the artery. 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 patient rescheduled. The catheter will then be removed 
and hemostasis achieved by manual compression or closure device. Each patient will be admitted for 
overnight care. The amount of contrast agent delivered to the patient during the procedure and dose of 
irradiation will be recorded as well as the time exposed to fluoroscopic imaging. All medications used 
during the procedure will be recorded, including pain management regime. The physician performing the 
procedure will grade the success of the procedure based on the following scale: 
 
Grade Lesion visualization/technical difficulty 
0 
Lesions not visualized, technically challenging procedure 
1 
Lesions sub-optimally visualized, procedure performed with some difficulty. 
2 
Lesions clearly visible, procedure performed without difficultly. 
 
Post Treatment: Following the DEBIRI procedure all patients will be observed for vital signs, femoral access 
site, pain management and fluid hydration for about 24 hours. The procedure for pain management will be 
at the investigator’s discretion. Blood for other labs, such as CBC or blood chemistries, may also be 
drawn on all patients prior to discharge. (See post treatment order from – appendix B). 
 
Discharge: Upon discharge from the hospital, patients will be given a suitable pain management regimen 
based on normal hospital procedure. Written instructions for pain management will be given to patients 
according to their clinical need. 
 
4.3 Definition of Dose-Limiting Toxicities 
 
Definition: This will be defined as any of the following toxicities occurring during the 3 weeks following 
each DEBIRI treatment that are judged as possibly, probably, or definitely related to study agent: 
 
 
≥ Grade 3 non-hematologic  toxicity  (excluding  nausea,  vomiting,  or diarrhea responding to 
symptomatic management or LFTs) 
 

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 
≥ Grade 3 nausea, vomiting and diarrhea that has not responded to maximal medical symptomatic 
management after ≥ 72hr will be considered a DLT 
 
 Grade 3 thrombocytopenia lasting > 5 days  
 
 
Grade 3 thrombocytopenia with  ≥ grade 3 bleeding at any site   
 
 
Grade 4 thrombocytopenia 
 
 
Grade 4 neutropenia lasting > 5 days or associated with fever or infection 
 
 
Grade 3 alkaline phosphatase increase lasting more than 2 weeks post 
procedure  
 
 
Grade 4 alkaline phosphatase at any time 
 
 
Grade 3 ALT, AST and/or bilirubin elevation will be classified as a DLT based on the following 
criteria: 
 
o persistent AST/ALT elevation of 5-10 times the upper limit of normal for more than 2 
weeks 
 
o Persistent AST/ALT elevation of >10-20 times the upper limit of normal for more than 1 
week 
 
 
Grade 4 ALT, AST and/or bilirubin elevation at any time. 
 
Dose escalation will proceed to the next cohort according to the following schema: 
 
# of Patients with 
DLT at a Given Dose 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped. This dose level will be declared to have 
exceeded the maximum tolerated dose Three additional patients will be 
entered at the next lowest dose level if only 3 patients were treated previously 
at that dose. 
 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is stopped, 
and this dose is declared to have exceeded the maximum tolerated dose. 
Three additional patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
<1 out of 6 
This is generally the MTD and recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 
 

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4.4 Supportive care guidelines 
 
 
Prophylactic use of granulocyte growth factors is not permitted. Use of these hematopoietic 
factors for grade 4 myelosuppression associated with infection or bleeding is permitted at the 
discretion of the treating physician and according to guidelines of the American Society of 
Clinical Oncology. Use of granulocyte growth factor support after neutropenic fever as a secondary 
prophylaxis is allowed per treating physician discretion. 
 
Use of erythropoietin is allowed at the discretion of the treating physician. 
 
Blood transfusions are allowed at the discretion of the treating physician. 
 
For management of treatment-related side effects, the use of standard supportive 
care including anti-emetics, intravenous hydration, and analgesics is strongly 
encouraged and will be decided upon by the treating physician. 
 
4.5  Concomitant medications 
 
Patients may not receive any other anticancer therapy while on study, including immunotherapy.  
Patients may not receive any other clinical investigational drug. 
 
If nausea, vomiting, or diarrhea occurs, effective symptomatic treatment can be initiated. For 
diarrhea, loperamide (Imodium®) should be used as standard therapy. 
 
4.6 Duration of therapy 
Therapy will continue per protocol until any of the following conditions occur 
 
Disease progression in treated lobe. 
 
Intercurrent illness that prevents further administration of treatment. 
 
Unacceptable adverse events. 
 
Patient decides to withdraw from study. 
 
General or specific changes in the patient's condition which render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
Judgment of the treating physician that further therapy is unlikely to be of benefit to the patient 
 
4.6.1 
Patient withdrawal 
Patients may be withdrawn from the study by the investigator or terminate their participation 
prematurely based on the following: 
 
 
Post-consent determination of ineligibility. 
 
Lack of therapeutic efficacy, as evidenced by progression of treated intra-hepatic disease 
(progression of untreated liver metastasis or extra-hepatic disease will not be considered 
failure of therapy). In the latter cases termination of the protocol will be determined 
according to section 8.1.2. For protocol purposes the patient will be classified based on 
the response rate of his treated liver lesions using RECIST criteria (as outlined in section 
8.1). 
 
Interval down staging of target lesions such that the patient would be an acceptable 
candidate for surgical resection. 
 
Physician’s judgment following an adverse event or unacceptable toxicity. 
 
Termination by the Sponsor, or a regulatory authority. 
 
Patients that require radiation therapy for local palliative purposes. 
 
Any other reason for withdrawal that the treating physician or patient indicates is in the overall best interest 
of the patient. 
 
4.7 Follow Up 

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The patient will be clinically evaluated approximately 30 days after completion of the trial. Telephone follow 
up at 3 month intervals for up to 2 years for survival and toxicity monitoring will be conducted. At 
treating physician discretion, patients may be followed more frequently for toxicities felt to be treatment-
related. 
 
5.0 Adverse Events 
5.1  Definitions 
5.1.1 Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, 
treatment or procedure regardless of whether it is considered related to the medical treatment or procedure 
(NCI CTEP Guidelines March 28, 2011). 
 
5.1.2 Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires inpatient hospitalization 
or prolongation of existing hospitalization (for > 24 hours), persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or is a congenital anomaly/ birth defect, or results in 
any important medical event that may not result in death, be life threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the above outcomes.  A “life-threatening” adverse 
event places the patient at immediate risk of death in the judgment of the investigator or sponsor. 
 
5.1.3 Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common Terminology Criteria for 
Adverse Events (CTCAE v.4.0) or study specific toxicity tables provided in the protocol define severity.  If 
not included in CTCAE v.4.0, severity is expressed in numerical grade using the following definitions: 
1. 
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2. 
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL. 
3. 
Grade 3: Severe-severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
4. 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. 
Grade 5: Death related to AE 
 
5.1.4 Attribution/Relationship to study drug  
1. 
Definite – clearly related 
2. 
Probable – likely related 
3. 
Possible – may be related 
4. 
Unlikely – doubtfully related 
5. 
Unrelated – clearly not related 
5.1.5 Expectedness 
 An Expected Adverse Event is one where the specificity or severity is consistent with the current 
information available from the resources. 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event is related to 
participation in the research is not consistent with either: 
1. 
The known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current IRB-approved informed consent 

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document, and (b) other relevant sources of information, such as product labeling and package 
inserts:  
 
OR 
 
2. 
The expected natural progression of any underlying disease, disorder, or condition of the subject 
(s) experiencing the adverse event and the subjects(s) predisposing risk factor profile for the adverse 
event.(OHRP Guidance on reviewing unanticipated problems 2007) 
 
5.2 Recording and Reporting Responsibilities 
 
5.2.1 Investigative site recording responsibilities: 
1. Upon identification of an AE or SAE, the site investigator will utilize the above 
definitions to properly classify the event.  Each category listed above must be recorded 
for each event. 
 
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and in 
progress reports with details about the grade and attribution of each episode, action 
taken with respect to the study drug, and the patient’s outcome will be recorded in the 
CRF.  All events will be recorded on case report forms for the duration of the study 
until they resolve. 
 
3. All SAEs will be recorded on the FDA MedWatch form 3500a.  After submitting the 
initial report it may be necessary to submit follow up reports should the event require 
further investigation. 
 
5.2.2 Investigative site reporting responsibilities: 
1. The investigator/ site is responsible to report all SAEs that occur on or after the first 
day of study treatment and up to 30 days after the last study treatment to the Sponsor 
within 24 hours of becoming aware of the event.   
 
2. Each investigator is responsible to report all AEs/SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC OCR reserves the right to request an event be 
reported to the IRB at their discretion.  Copies of events reviewed by email to 
SAE.FCCC@fccc.edu. 
 
3. If the investigator or IRB feels the event warrants a revision to the informed consent 
that was not already initiated by the OCR, draft revisions will be made in track 
changes and submitted to the OCR for consideration.  Any consent revisions must 
receive OCR approval prior to submission to the IRB. 
 
4. Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call Study Monitor for confirmation with the Sponsor-Investigator. 
 
5. If the results of an investigator or OCR investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report the 
event following the above guidelines based on the date the determination is made. 
 
6. Copies of all related correspondence and reporting documents must be submitted to 
the ISRU and will be maintained in the trial master file. 
 
 

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Participating sites should report events to: 
 
 
Investigator-Sponsored Research Unit 
 
Office of Clinical Research 
  
Fox Chase Cancer Center 
 
SAE.FCCC@fccc.edu 
 
 
5.2.3 Sponsor Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the 
event.   
i. 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
ii. Possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
iii. Serious (refer to above definition) or otherwise one that suggests that the research 
places subjects or others at a greater risk of physical or psychological harm than 
was previously known or recognized. 
 
2. If the adverse event requires modification of the study protocol and informed consent, 
these changes will be provided to all participating institutions in the form of an 
amendment from the ISRU for each site’s IRB of record along with the report of the 
adverse event.   
 
3. Copies of all related correspondence and reporting documents will be maintained in a 
centralized regulatory file for this study within the OCR. 
 
4.   SAEs that are related, unexpected, fatal, or life-threatening are reportable through the 
Food and Drug Administration (FDA) MedWatch program by telephone or fax no 
later than 7 calendar days after initial receipt of the information.  Further information 
on the timing of submissions are as directed by FDA guidelines 
(http://www.fda.gov/medwatch/index.html).  Serious, unexpected events that suggest 
significant clinical risk will be submitted to within 15 calendar days after initial 
receipt of this information. 
 
Food and Drug Administration (FDA) 
Center for Devices and Radiological Health  
Document Mail Center – W066-G609 
10903 New Hampshire Avenue 
Silver Spring, MD 20993-0002 
 
In addition, any Medical Device Report (MDR) may be faxed to FDA 
following approval. A request for approval of facsimile reports can be 
obtained by calling 301-827-7537 
 
AND 
 

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Within 24 hours of becoming aware: 
 
Biocompatibles Inc., a BTG International Group Company 
pharmacovigilance@btgplc.com 
 
Any serious adverse events which occur during the clinical study or within 
30 days of receiving the last dose of study medication, whether or not 
related to the study drug, must be reported. 
 
6.0 DEBIRI formulation and procurement 
 
LC Bead microspheres are produced from a biocompatible polyvinyl alcohol (PVA) hydrogel that 
contains sulphonate groups which allow the controlled loading and delivery of chemotherapeutic 
drugs.  LC Bead occludes the blood flow to the target tissue and delivers a local and sustained dose 
of drug direct to the tumor.  LC bead is 510K cleared by the FDA for the embolization of 
hypervascularized tumors and arteriovenous malformations (AVMs) only. Loading of irinotecan 
into the LC Bead is considered investigational in the US. 
 
LC Bead is biochemically identical to DC Bead which received CE mark approval in 2003 
and is indicated for the treatment of malignant hyper-vascularised tumors and loading with 
doxorubicin. DC Bead may also be loaded with Irinotecan for the treatment of metastatic 
colorectal cancer. 
 
The intention of this study is to use LC Bead loaded with irinotecan for the purpose of: 
embolization of vessels supplying malignant metastatic tumor(s) and delivery of a local, 
controlled, sustained dose of irinotecan to the tumor(s) 
 
LC Bead comprise a range of hydrogel microspheres that are biocompatible, hydrophilic, non 
resorbable and precisely calibrated. Various beads sizes are available for use ranging from 70 to 
900µm. In this study we will utilize the smallest size beads (70-150 µm- Yellow-black label – 
M1), which are thought to have improved penetration to the tumor and therefore more targeted 
drug delivery. 
 
Upon loading with irinotecan, LC Bead undergo a slight decrease in size, up to 30% when 
loading at 50mg/ml. At the time of use, LC Bead will be mixed with irinotecan according to 
the instructions for loading. LC Beads are suitable for loading irinotecan Solution (20mg/ml) 
ONLY. With the use of M1 LC beads it is recommended that the user will ensure that the 
size is appropriate for the intended vasculature. In addition, patients should be carefully 
monitored for signs of non-target embolization such as hypoxia or CNS changes. Finally the 
user should consider upsizing of the beads if angiographic evidence of embolization does not 
appear quickly during delivery. 
  
Drug loading instructions: These are the loading instruction for all dose levels on this study. 
1. Remove as much saline as possible from a vial of LC Bead using a syringe with a small 
gauge needle. 
2. Using a syringe and needle add the appropriate amount of Irinotecan solution 
(solution concentration of 20mg/ml) directly to the vial of LC Bead, as outlined in the 
table below: 

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Irinotecan dose 
Amount to be added to LC beads 
50mg 
2.5ml 
75mg 
3.75ml 
100mg 
5ml 
 
3. Agitate the LC Bead / Irinotecan solution gently to encourage mixing then allow 
standing. The beads will turn a turquoise color as the loading progresses. 
4. The minimal incubation time is 2 hours for 98% absorption, but may be up to 5 hours 
for 100% absorption. 
5. Prior to use, transfer the LC Bead loaded with irinotecan to a syringe and expel the 
excess supernatant using a filter needle. Add 5ml sterile water, in order to minimize 
irinotecan elution, and add 10-20 cc of contrast media per 1ml/cc of irinotecan 
loaded beads. Invert the syringe gently to obtain an even suspension of DC Bead. 
 
LC Bead loaded with irinotecan is physically and chemically stable for up to 14 days if stored 
in a fridge at 2-8°C or 4 hours at room temperature in the absence of non-ionic contrast 
media. However the allocation of a shelf-life longer than 4 hours at room temperature or 24 
hours if stored in the fridge is the responsibility of the user and dependent upon the use of 
controlled aseptic conditions for preparation. The irinotecan loaded bead solution will be mixed 
with non-ionic contrast only at the time of injection into the patient via a properly placed 
catheter or microcatheter. 
 
In this protocol the beads will be loaded within 2 hours of the procedure. Discard any unused 
LC Bead loaded with irinotecan. 
 
7.0 Study Calendar 
All pre-study/baseline evaluations except serum pregnancy test may be performed up to 28 days prior to 
registration. A timetable of relevant assessments is provided in the table below for uni-lobar and bi-
lobar disease (all tests can be performed within ±2 days of this schedule). This timetable contains the 
schedule for two treatments 3 weeks apart followed by CT on week 8. The schedule can be repeated 
for additional treatment in appropriate cases (section 4.2.1). 
 
Based on experience from previous studies using DEBIRI there exists a risk of post 
procedure transient edema, which may confound the response evaluation by RECIST 
criteria. In case of disease progression on week 8 imaging the patient will be followed 
with repeat CT at 12 weeks to rule out the possibility of edema accounting for the 
progressive disease. 
 
 

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Study Calendar 
 
Pre- 
Study 
Day 
1 (± 2)i 
Day 
 2i 
Day 
8 
Day 
15 
Day 
22  
(± 2)i 
Day 
 23i 
Day 
29 
Day 
36 
Day 
57 
EOTh 
Follow Up 
for 
Survivalj 
Planned treatment 
(Unilobar/dominant lesion in 
bilobar disease) ± 2 daysa 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X----------------------------------------------------------------------------------------------------------------X 
 
Physical examb 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
X 
 
 
 
 
X 
 
CBC w/diffc 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistryc 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CEAd 
X 
 
 
 
 
 
 
 
 
X 
X 
 
PT/INR/PTTe 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Adverse  Event Evaluations 
 
X----------------------------------------------------------------------------------------------------------------X 
 
CT scan of the chest  
abdomen & pelvis f 
 
X 
 
 
 
 
 
 
 
 
XK 
 
 
B-HCGg 
X 
 
 
 
 
Hepatic angiogram 
 
X 
 
 
 
a. Patients with unilobar disease will be treated on day 1 ± 2 days and 3 weeks later on day 22 ± 2 days with CT 8 weeks after the 
initial treatment. Patient with bilobar disease will receive treatment to the dominant lobe on day 1 ± 2 days and 3 weeks later on day 
21 ± 2 days with CT 8 weeks after the initial treatment.  Patients without evidence of progression will be candidates for 
treatment of the non-treated lobe for 2 treatments 3 weeks apart.    
b. Medical history and physical examination will be obtained prior to each treatment according to the treatment schedule (±2 days). Pre-
treatment medical history can consist of interval history. 
c. CBC and Chemistry are to be obtained on the day before treatment (±2 days), and every week while on the study (±2 days). Additional 
blood tests should be performed per the discretion of the treating physician. Blood work obtained within ±2 days may be used. 
d. CEA evaluation will be obtained at the beginning of the study and with each imaging evaluation. 
e. PT/INR/PTT only required prior to each procedure. 
f. Additional imaging may be obtained at discretion of treating physician (e.g. MRI, PET scan, etc.). Alternative imaging of liver (ie 
MRI in place of CT scan) is acceptable when preferred by treating physician. MRI of the liver may be used as a substitute for a 
CT scan for patients with creatinine 1.5-2.0 who are at risk for contrast induced nephropathy. Diabetic patients treated with 
medications from the biguanides family such as Metformin would be required to hold their medicine for 1 day before and 2 days 
after their scheduled CT scan. 
g. Serum pregnancy test (women of childbearing potential) within 72 hours before treatment. 
h. Off-study evaluation. Two consecutive measurements taken at least 4 weeks apart must be used to document partial or complete 
responses in patients meeting these criteria with measurable disease. Follow-up details are available in section 4.7. 
i.    Following the procedure the patient will be admitted for overnight observation. On day 1 post treatment blood work including CBC 
and CMP will be obtained along with physical examination. 
j.    Patients will be followed up for overall survival status. Medical evaluation is NOT required to determine status. The patient will be 
clinically evaluated approximately 30 days after completion of the trial. Telephone follow up at 3 month intervals for up to 2 years for 
survival and toxicity monitoring will be conducted. At treating physician discretion, patients may be followed more frequently for 
toxicities felt to be treatment-related. 
k.   Patients who demonstrate progression with their Day 57 (week 8) CT scan should have a repeat CT scan at week 12 to rule out 
inflammation as a source of tumor enlargement. 
 
 

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8.0 Measurement of Effect 
 
Although response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria. For the purposes of this study, all patients 
will be evaluated for response 8 weeks following the administration of DEBIRI, response 
rate will be calculated based on the treated lobe only. In addition to a baseline scan, 
confirmatory scans must be obtained at least 4 weeks following the initial documentation of 
complete or partial response. In cases of disease progression at 8 weeks, repeat CT will be 
done at 12 weeks to exclude the possibility of treatment related transient edema 
accounting for disease progression. 
 
Definitions 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
version 1.1 (50, 51) . RECIST 1.1 limits the number of measurable lesions in an organ to 2 
and the total number of measurable lesions to 5. Since response is being evaluated in this 
study only in the treated lobe of the liver, we will measure response on up to 5 total 
lesions in that lobe of liver. 
 
Patients must have at least one measurable lesion, defined as >20mm using CT or MRI, or 
>10mm using spiral CT. Where disease is restricted to a solitary lesion, its neoplastic 
nature must be confirmed by cytology/histology. 
 
Baseline measurements must be taken not more than 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 will be identified. Those with the 
largest diameters should be included. 
 
A sum of the longest dimension (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. 
Change on the sum of these dimensions affords some estimate of change in tumor size 
and hence therapeutic efficacy. 
8.1 Response Criteria 
 
8.1.1 Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions, or disappearance of arterial 
enhancement in the target lesion 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD. 
Progressive Disease (PD): 
1. At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started. 
2. The appearance of one or more new lesions. 
3. Death  due  to  disease  without  objective  evidence  of 
progression 

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Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
Symptomatic Deterioration 
Is defined as a global deterioration in health status attributable 
to the disease requiring a change in therapy without objective 
evidence of progression. 
In evaluable for Response 
Is defined as having no repeat tumor assessments following 
initiation of study therapy for reasons unrelated to symptoms or 
signs of disease 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion (51). 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
 
8.1.2 
Progressive disease outside of the liver: 
For protocol purposes new or increasing lesions outside of the liver will not be considered 
progressive disease. However, the protocol will be discontinued in the following cases in which 
the extent of disease limits further benefit of liver-directed treatment: 
• 
Diffuse pulmonary disease 
• 
Diffuse peritoneal carcinomatosis 
• 
Diffuse lymph node involvement 
• 
Diffuse bone metastases with bone marrow compromise 
• 
New metastatic disease resulting in organ dysfunction, or intractable pain. 
The treating physician may elect to terminate participation in this protocol in other cases in which 
alternative therapy is indicated. 
 
8.2 Duration of response 
 
For purposes of this study, response rate will be calculated based on the treated lobe only. 
 
Overall response: The duration of overall response is measured from the time measurement 

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criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
 
Stable Disease: Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment 
started. 
 
8.3 Time to progression 
 
Time to progression (TTP) is defined as the duration of time from start of treatment to 
progression in the treated lobe. 
 
9.0 Statistical Considerations: 
The study is a phase I study with a total of 3 dose levels. For the dose-escalation portion of the 
study, approximately 9 evaluable subjects will be required if DLTs do not occur (3 subjects in 
each of the dose cohorts, 50, 75, 100). If a DLT does occur among the first 3 subjects in a cohort, 
3 additional subjects will be added to the cohort. In case 2 or more DLTs occur in a cohort, a total 
of 6 subjects will be treated at the preceding dose, which will be evaluated for MTD. At a 
minimum we will enroll 3 patients at each dose level with an expansion of the last dose level 
with 14 additional patients. Therefore we are estimating accrual of 9-30 patients under this 
protocol. For each dose-escalation arm during Phase 1 the evaluable population for DLT 
includes all subjects enrolled in the dose-escalation arm, who received at least 1 full cycle of 
DEBIRI. The Safety Population includes all subjects who receive treatment with DEBIRI. 
 
At the dose expansion level 10% of DLT will be acceptable and 33% will be unacceptable. We 
would terminate the study if ever 4 DLTs occur including 1 that would have occurred in the MTD 
cohort of 6 patients. The chance of declaring the treatment too toxic when only 10% toxic is about 
9% while the chance of this decision when the true toxicity id 33% is about 85%. 
 
Reporting and Exclusions 
 
9.1.1 Evaluation of toxicity. 
All patients will be evaluable for toxicity from the time of their first treatment with 
DEBIRI until study completion. Toxicity reports will be carried out as detailed in section 
5.0. 
 
9.1.2 Evaluation of response. 
All patients with measurable disease included in the study will be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are ineligible.  
Each patient will be assigned one of the following categories: 
1) Complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 8) unknown (not assessable, insufficient data). (47) 
 
9.2 Data Safety Monitoring Plan 
 

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9.2.1 Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the ISRU will collect and report data to 
the study Sponsor-Investigator who will review these data on a regular basis at a rate 
dependent on subject accrual.  All serious adverse events (SAEs) will be reviewed on a 
real time basis first by the study site PI and subsequently by the ISRU and Sponsor-
Investigator as applicable. 
 
9.2.2 Data & Safety Monitoring Committee   
Interim analysis of toxicity, outcome and ongoing scientific investigations may be 
performed at least every 6 months by the Fox Chase Cancer Center Data Safety 
Monitoring Board (FCCC DSMB).  In this capacity the FCCC DSMB will serve as an 
advisory committee to the Sponsor-Investigator.  The FCCC DSMB will review those 
aspects of this trial that are outlined in the responsibilities section of the Data and Safety 
Monitoring Plan (DSMP).  If the committee decides that changes should be made to this 
trial, it will make recommendations in writing to the Study Sponsor-Investigator, the 
Associate Director of Clinical Research, and the Protocol Management Executive 
Committee, which, in turn, have the authority to approve or disapprove these 
recommendations.  These changes will be discussed with the Study Sponsor-Investigator 
before they are implemented.  These changes may include early termination of accrual.  
Other changes might include altering the accrual goals or changing the eligibility criteria 
for the trial. 
 
10.0 Administrative   
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
10.1 Data Reporting 
The FCCC Study Monitor will request case report forms to be completed within 2 weeks 
of the protocol visit.  Participating sites are responsible to respond to queries prior to the 
next scheduled monitoring visit.   
 
The ISRU is responsible for compiling and submitting data to the Sponsor-Investigator 
and statistician on an ongoing basis for monitoring as described in the data safety 
monitoring plan and reporting to the Data and Safety Monitoring Board. 
 
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, 
such as case report files, produced will be stored in a secure location.  
 
The ISRU is responsible for distributing and tracking review of all IND/IDE Action 
Letters, Safety Reports, study specific Serious Adverse Events 
 
10.2 Retention of Records   
Time points for the retention of records are described in detail in the contract between 
the grantor and the OCR and passed on to the participating site.  Please refer to the study 
specific terms for specific time points.  In all cases the Study Monitor must be notified 

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of any plans to move records to an offsite location prior to doing so. 
 
10.3 Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol.  The 
agent may not be transferred to any party not participating in the clinical trial. 
 
 
10.4 Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study.  A copy of the informed consent documents must be provided 
to the patient or the patient’s legally authorized representative.  If applicable, they will be 
provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file according to site policy. 
  
 
 

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Appendix A – Pre-treatment orders: 
 
 
1. Ancef 1 gram IVPB (If PCN allergy use Vancomycin 500mg IVPB) 
2. Flagyl 500mg IVPB 
3. Benadryl 50mg IVP 
4. Decadron 10mg IVP (can be omitted if patient is diabetic, at the discretion of the 
treating physician) 
5. Zofran 8mg IVP. 
6. Normal saline 100cc/hr IV. Patients with creatinine 1.5-2.0 should receive an 
additional bolus of 1000ml normal saline IV prior to the 
procedure. 
7. Sedation: Fentanyl and Versed for conscious sedation. 
8. If the patient is diabetic receiving therapy with drugs from the Biguanides family (i.e. 
Metformin), the physician should verify that the patient has been off the drug for 1 day 
prior to the procedure. 

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Appendix B– Post-treatment order form: 
 
 
Admit to medicine for overnight observation following procedure. 
 
1. Bed rest from 
to 
. 
2. Elevation of the head of the bed by 10 degrees each hour up to 30 degrees. 
3. Monitor for hematoma and pulse at the puncture site with vital signs q15min for 
the first hour; every 30 min for the following 2 hours; every 1 hour for the 
next 3 hours. 
4. Apply direct pressure in the presence of expanding hematoma and contact 
treating interventional radiologist immediately. 
5. Call treating interventional radiologist immediately for loss of pulse or 
new   
or   increasing   arterial   insufficiency   (coldness,   blue 
discoloration,  numbness,  pain,  tingling)  in  the  extremity  of  the puncture 
site. 
 
Fluid: 
1000ml D51/2 NSS @ 125 cc/hr 
Anti-emetics 
Zofran 8mg IVP PRN for nausea 
Analgesics 
Dilaudid 1mg IV push Q 2H PRN for pain 
Labs – on the morning 
following procedure 
CBC 
CMP 
 
Discharge decision will be made by the treating interventional radiologist during 
admission. Clinically stable patients may be discharged home after 24hr observation 
and follow up as an outpatient for repeat blood work in 1 week. 
 
For diabetic patients receiving therapy with drugs from the Biguanides family (i.e. Metformin) 
they should be instructed to hold the drug for 2 days following the procedure. 

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Appendix C - DEBIRI adverse event profile 
 
Table 1: Articles reporting complications/adverse events in mCRC patients treated using DC 
Bead with Irinotecan 
 
Table reproduced with permission from Biocompatibles UK Ltd 
Source: Biocompatibles Embolic Agents - Adverse Events Analysis (REVISION 3) July 2011 
Reference 
Population 
Number of Patients 
No of Treatments 
Fiorentini 2008 
mCRC 
20 
35 
Fiorentini 2009b 
mCRC 
20 
40 
Fiorentini 2009a 
mCRC 
35 
72 
Martin 2009b 
mCRC Cholangiocarcinoma Other 
109 
187 
Martin 2009d 
mCRC 
55 
99 
Martin 2009c 
mCRC 
30 
57 
Bower 2010 
mCRC 
55 
90 
CA1011 
mCRC 
11 
40 
Aliberti 2006 
mCRC 
10 
18 
Aliberti 2009 
mCRC 
82 
185 
Yadavali 2009 
mCRC 
24 
28 
O’Grady 2009 
mCRC - resectable 
7 
7 
Narayanan 2010 
mCRC 
16 
26 
Total Number of Patients 
304 
585 
 
Table X: Number of Complications reported in the literature and overall incidence for DC 
Bead and Irinotecan. 
Table reproduced with permission from Biocompatibles UK Ltd 
Source: Biocompatibles Embolic Agents -  Adverse Events Analysis (REVISION 3 ) July 2011 
Event 
N (%) 
Overall Incidence N (%) 
Reference 
Acute Pancreatitis 
1/82 (1.2%) 
1/20 (5%) 
1/24 (4.2%) 
3/304 (1.0%) 
Aliberti 2009 
Fiorentini 2008 
Yadavali 2009 
Alopecia 
7/10 (70%) 
7/304 (2.3%) 
Aliberti 2006 
Anaemia 
1/55 (1.8%) 
2/35 (5.7%) 
3/304 (1%) 
Martin 2009d 
Fiorentini 2009a 
Anorexia 
3/55 (5%) 
1/16 (6%) 
4/304 (1.3%) 
Martin 2009d 
Narayanan 2010 
Asthenia 
(G1-2) 
8/10 (80%) 
7/35 (20%) 
1/11 (9.1%) 
16/304 (5.3%) 
Aliberti 2006 
Fiorentini 2009a 
CA1011 
Cholecystitis 
1/55 (1.8%) 
1/304 (0.3%) 
Martin 2009d 
Constipation 
1/11 (9.1%) 
1/304 (0.3%) 
CA1011 
Diarrhoea 
1/35 (2.8%) 
1/304 (0.3%) 
Fiorentini 2009a 
Dehydration 
1/55 (1.8%) 
1/304 (0.3%) 
Martin 2009d 
Dyspnoea 
1/11 (18.1%) 
1/304 (0.3%) 
CA1011 
Fatigue 
1/16 (6%) 
1/304 (0.3%) 
Narayanan 2010 
Gastritis 
1/55 (1.8%) 
1/304 (0.3%) 
Martin 2009d 
Hypertension 
1/55 (1.8%) 
1/11 (9.1%) 
2/304 (0.7%) 
Martin 2009d 
CA1011 
Haematoma 
1/7 (14%) 
1/24 (4.2%) 
2/304 (0.7%) 
O’Grady 2009 
Yadavali 2009 

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Infection 
1/11 (9.1%) 
1/304 (0.3%) 
CA1011 
Insomnia 
1/16 (6%) 
1/304 (0.3%) 
Narayanan 2010 
Leucopenia 
2/35 (5.7%) 
2/304 (0.7%) 
Fiorentini 2009a 
Liver Abscess 
1/10 (10%) 
2/304 (0.7%) 
Aliberti 2006 

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Event 
N (%) 
Overall Incidence N (%) 
Reference 
1/20 (5%) 
Fiorentini 2008 
Liver dysfunction/failure 
4/55 (7.3%) 
4/304 (1.3%) 
Martin 2009d 
Musculoskeletal chest pain 
1/11 (9.1%) 
1/304 (0.3%) 
CA1011 
Pain 
2/11 (18.1%) 
2/304 (0.7%) 
CA1011 
Palpitations 
1/11 (9.1%) 
1/304 (0.3%) 
CA1011 
Post Embolisation Syndrome 
URQP
URQP (G2)
(G3)
10/10 (100%) 
74/185* (40%) 
10/20 (50%) 
5/20 (25%) 
99/304 (33%) 
Aliberti 2006 
Aliberti 2009 
Fiorentini 2008 
Fiorentini 2008 
Abdominal Pain 
5/16 (31%) 
11/35 (31%) 
6/11 (55%) 
22/304 (7.2%) 
Narayanan 2010 
Fiorentini 2009a 
CA1011 
Fever 
(G2) 
148/185* (80%) 
20/20 (100%) 
7/35 (20%) 
175/304 (58%) 
Aliberti 2009 
Fiorentini 2008 
Fiorentini 2009a 
Nausea 
Nausea (G2) 
Nausea/Vomiting (G2) 
5/99* (5%) 
6/16 (37%) 
6/11 (55%) 
148/185* (80%) 
20/20 (100%) 
185/304 (61%) 
Martin 2009d 
Narayanan 2010 
CA1011 
Aliberti 2009 
Fiorentini 2007 
Inc Transaminases (G2-3) 
130/185* (70%) 
130/304 (43%) 
Aliberti 2009 
PES (nausea/emesis) 
1/11 (9%) 
1/304 (0.3%) 
Bower 2010 
Pneumonia 
1/55 (1.8) 
1/304 (0.3%) 
Martin 2009d 
Vomiting 
2/16 (12%) 
1/7 (14%) 
14/35 (40%) 
8/10 (80%) 
3/55 (5%) 
7/11 (64%) 
22/304 (7.2%) 
Narayanan 2010 
O’Grady 2009 
Fiorentini 2009a 
Aliberti 2006 
Martin 2009d 
CA1011 
WBC Increase 
1/11 (9.1%) 
1/304 (0.3%) 
CA1011 
Transient Ischaemic Attack 
1/24 (4.2%) 
1/304 (0.3%) 
Yadavali 2009 
*Denominator is procedures not patients in these cases 

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Table 2: Overall incidence of complications relating to DC Bead and Irinotecan in mCRC 
– comparison with Events documented in the Baseline Risk Document for cTACE and systemic 
irinotecan 
Table reproduced with permission from Biocompatibles UK Ltd 
Source: Biocompatibles Embolic Agents - Adverse Events Analysis (REVISION 3 ) July 2012 
Event 
Overall N (%) 
Baseline Risk N (%) 
Reference 
Anaemia 
3/304 (1%) 
2/26 (7.6%) 
4.5% (G3-4) 
Bavisotto 1999 
Pfizer prescribing info 2008 
Asthenia (G1-2) 
16/304 (5.3%) 
10/11 (91%) (G1-2) 
69% (G1-2) 
14% (G3-4) 
Voigt 2002 
Pfizer prescribing Info 2008 
Constipation 
1/304 (0.3%) 
1/26 (3.8%) 
32% (G1-2) 
0.4% (G3-4) 
Bavisotto 1999) 
Pfizer prescribing Info 2008 
Diarrhoea 
1/304 (0.3%) 
1/11 (9%) 
5/41 (12%) 
9/50 (17%) 
1/26 (3.8%) 
83% (G1-2) 
31% (G3-4) 
Voigt 2002 
Pajkos 1998 
Salman 2002 
Bavisotto 1999  
Pfizer prescribing info 2008 
Dyspnoea 
1/304 (0.3%) 
2/26 (7.6%) 
22% (G1-2) 
2.2% (G3-4) 
Bavisotto 1999  
Pfizer prescribing info 2008 
Infection 
1/304 (0.3%) 
2/26 (7.6%) 
14% (G1-2) 
0.4% (G3-4) 
Bavisotto 1999  
Pfizer prescribing info 2008 
Insomnia 
1/304 (0.3%) 
1/26 (3.8%) 
19% (NCI G1-4) 
Bavisotto 1999 
Pfizer prescribing info 2008 
Leucopenia 
2/304 (0.7%) 
2/41 (5%) 
97% (G1-2) 
22% (G3-4) 
Pajkos 1998 
Pfizer prescribing info 2008 
Pneumonia 
1/304 (0.3%) 
1/26 (3.8%) 
3.6% (G1-2) 
1.3% (G3-4) 
Bavisotto 1999  
Pfizer prescribing info 2008 

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Table 3: Overall incidence of complications relating to DC Bead and Irinotecan in mCRC 
– comparison with Events documented in the Baseline Risk Document for cTACE and systemic 
irinotecan 
 
Table reproduced with permission from Biocompatibles UK Ltd 
Source: Biocompatibles Embolic Agents - Adverse Events Analysis (REVISION 3 ) July 2012 
 
Event 
Overall N (%) 
Baseline Risk N (%) 
Reference 
Acute Pancreatitis 
3/304 (1%) 
(1.7-4%) 
Ozcinar 2009 
Cholecystitis 
1/304 (0.3%) 
1/21 (5%) 
Wasser 2005 
Fatigue 
1/304 (0.3%) 
“Common” in 40 
Sanz-Altamira 1997 
Gastritis 
1/304 (0.3%) 
3/26 (11.5%) 
Bavisotto 1999 
Haematoma 
2/304 (0.7%) 
1/54 (2%) 
Swanson 2002 
Liver Abscess 
2/304 (0.7%) 
9/3878 (<1%) 
3/2012 (0.15%0 
2/176 (1.1%) 
1/278 (0.4%) 
2/72 (2.7%) 
Ong 2004 
Xia 2006 
Chen 1999 
Kiely 2006 
Farinati 1996 
Liver dysfunction/failure 
4/304 (1.3%) 
2/102 (2%) 
PV 2010 
Post Embolisation Syndrome 
Abdominal Pain
Fever 
Nausea 
Nausea/Vomiting
99/304 (33%) 
22/304 (7.2%) 
175/304 (58%) 
185/304 (61%) 
1/304 (0.3%) 
(86%) 
91/126 (72.2%) 
Gd'ETCH 1995 
Chabrot 2009 
Inc Transaminases (G2-3) 
130/304 (43%) 
135/145(93%) 
Wigmore 2003 
WBC Increase 
1/304 (0.3%) 
Observed in TACE 
Wagnetz 2010 
Musculoskeletal chest pain 
1/304 (0.3%) 
Not documented 
Palpitations 
1/304 (0.3%) 
Not documented 
Hypertension 
2/304 (0.7%) 
Not documented 
Transient Ischaemic Attack 
1/304 (0.3%) 
Not documented 

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