Chemoembolization, Irinotecan Bead, Second Line Chemotherapy Treatment of Unresectable Metastatic Colorectal Cancer

There are many treatments for metastatic colorectal cancer to the liver, and both the
application and outcomes are highly dependant on the patients disposition. Whilst resection
results in the best long term survival, it is often not a viable treatment option.

Irinotecan Bead is an embolization device intended to treat colorectal cancer metastases of
the liver. As an adjunct to this, irinotecan is present in the microspheres which is released
in a controlled manner into the local environment of the tumor. Irinotecan Bead is a
combination of an approved embolization device and an approved chemotherapy agent. The device
is a PVA based embolization agent from Biocompatibles UK Ltd, and the irinotecan is sourced
from an FDA approved supplier.

Irinotecan, a topoisomerase inhibitor, was the first systemic chemotherapy drug other than
5-Fluorouracil (5-FU) to demonstrate significant activity in the treatment of metastatic
colorectal cancer. Irinotecan is approved for use in combination with 5-FU/folinic acid in
patients without prior chemotherapy, and for the second-line treatment of metastatic
colorectal cancer as a single agent in patients who have failed an established 5-FU
containing treatment regimen.

The purpose of this combination device as a treatment for cancer in the liver is twofold:

(i) Nutrient and oxygen starvation of the tumor. (ii) Minimization of chemotherapy wash-out
with prolonged contact with tumor tissue.

Irinotecan Bead can be administered intra-arterially in the same manner as conventional TACE.
The benefit of this product is that TACE is achieved in a simpler one-step procedure by
precisely embolizing the arteries feeding the tumor, and as an ancillary action, the
Irinotecan Bead may release a controlled dose of irinotecan into the tumor bed.

The potential benefits of Irinotecan Bead could be significant since a sustainable release of
chemotherapy over time could have a greater effect on tumor mass, because optimal therapeutic
efficacy of Irinotecan (an S phase-specific cytotoxic drug) generally requires prolonged
exposure of the tumor to concentrations exceeding a minimum threshold.

Studies of low-dose, protracted administration of Irinotecan and other camptothecin analogues
in mice bearing xenografts of human tumors have shown less toxicity and equal to or better
antitumor activity than shorter, more intense dosing schedules. With the proposed device, the
in-vivo and pre-clinical data shows that there is reduced systemic levels of Irinotecan, when
delivered to tumorous tissue following embolization, and a longer, sustained concentration of
the active metabolite, SN-38.

This is a multicentre, open labeled, prospective, randomized, controlled phase II study
designed to assess the clinical performance of chemoembolization with Irinotecan Bead in
combination with intravenous chemotherapy (irinotecan monotherapy) versus intravenous
chemotherapy alone in the treatment of unresectable liver metastases in patients with
colorectal cancer who previously failed first line chemotherapy.

The primary endpoint will be Progression Free Survival measured from the first treatment in
this study until progression. Additional endpoints will be Pharmacokinetics of systemic
Irinotecan and SN-38 (Irinotecan Bead treatment for feasibility group only); Tumor Response
measured according to RECIST; Local tumor response (extent of necrosis in the treated
lesions); hepatic progression free survival measured from first treatment until progression
in the liver; change in tumor markers (CEA and optional CA19-9); performance status and
overall survival assessed by telephone follow-up. Safety will be measured by assessing
Adverse Events and Toxicity according to the NCI CTCAE v3.0 criteria.

Approximately 70 patients will be enrolled. The first 10 patients will be enrolled in a
feasibility safety evaluation in the test arm of the trial.

Inclusion Criteria:

- Patients with confirmed diagnosis of stage IV colorectal cancer with unresectable
liver metastases (primary tumor may be present)

- Patients with at least one measurable liver metastases, with size > 1cm (RECIST
criteria)

- Patients with liver dominant disease defined as ≥50% tumor body burden confined to the
liver

- Patients with patent main portal vein

- Performance status ≤ 2 ECOG

- Life expectancy > 6 months

- Aged ≥18 years

- Patient has failed (discontinued for progression or toxicity) one prior line of
chemotherapy for metastatic disease, preferably oxaliplatin-based (e.g. FOLFOX,
CAPOX). Note that substitutions of oral versus IV 5-FU formulations, changes in 5-FU
schedules, or discontinuations/re-starting of the same chemotherapy drugs will not be
considered as separate lines of therapy, nor will the addition of "biologics" such as
bevacizumab, cetuximab, or panitumumab

- Patient has no previous treatment with irinotecan

- At least 4 weeks since last administration of last chemotherapy and /or radiotherapy

- Hematologic function: ANC ≥ 1.5 x 109/L, platelets ≥75 x10-9/L, INR <1.5 (patients on
therapeutic anticoagulants are not eligible)

- Adequate liver function as measured by: Total bilirubin ≤ 2.0mg/dl, ALT, AST ≤5 times
ULN, albumin ≥2.5g/dl,

- Adequate renal function (creatinine ≤ 2.0mg/dl)

- Women of child bearing potential and fertile men are required to use effective
contraception (negative serum βHCG/urine test for women of child-bearing age)

- Signed, written informed consent

Exclusion Criteria:

- Patient eligible for curative treatment (i.e. resection or radiofrequency ablation).
Note: resectability is defined as a single tumor <5cm with adequate liver function
defined: Total bilirubin ≤ 2.0mg/dl, ALT, AST ≤5 times ULN, albumin ≥2.5g/dl

- Contraindications to irinotecan:

- Chronic inflammatory bowel disease and/or bowel obstruction

- History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate,
lactic acid or to any of the excipients of Camptosar

- Severe bone marrow failure

- History of Gilbert Syndrome (specific testing not required)

- Concomitant use with St John's Wort (Hypericum)

- Active bacterial, viral or fungal infection within 72 hours of study entry

- Women who are pregnant or breast feeding

- Previous irinotecan based therapy for metastatic disease

- Patients' whose only measurable disease is within an area of the liver previously
subject to radiotherapy

- Allergy to contrast media that cannot be managed with standard care (e.g. steroids)

- Presence of another malignancy with the exception of cervical carcinoma in situ and
stage I basal or squamous carcinoma of the skin

- Contraindicated for MRI or CT

- Patients previously treated with transarterial embolization (with or without
chemotherapy)

- Any contraindication for hepatic embolization procedures:

- Large shunt as determined by the investigator (pretesting with TcMMA not required)

- Severe atheromatosis

- 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 patient at undue risk, that would preclude the safe use of
chemoembolization or would interfere with study participation