Feasibility and Prospective Randomized Study of Transarterial Chemoembolization Using Irinotecan Bead in Combination With Second Line Chemotherapy in the Treatment of Patients With 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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression Free Survival
Wells Messersmith, MD
University of Colorado, Denver
United States: Food and Drug Administration
|University of Colorado Cancer Center||Denver, Colorado 80262|
|Northwestern University||Chicago, Illinois 60611|
|Lahey Clinic||Burlington, Massachusetts 01805|