Irinotecan -Eluting LC Bead-M1 (DEBIRI-M1) for Patients With Liver Metastases From Colorectal Cancer

Study Overview
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Brief Summary
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Purpose: The purpose of this study is to determine the feasibility and safety of using small beads (70-150 micron in place of 100-300 micron) to deliver chemotherapy into the liver to treat patients with liver lesions from colorectal cancer. The beads (LC-Bead M1) will be loaded with irinotecan (DEBIRI-M1), and used to administer transarterial chemoembolization (TACE). Eligibility: Patients with liver cancer from colorectal cancer. Study Overview/ Treatment: DEBIRI, loaded with irinotecan, is a device that utilizes tiny beads (70-150 microns) to deliver chemotherapy agents into liver tumor(s) via the hepatic artery. This device allows for continuous release of irinotecan into the liver tumor tissue(s) causing necrosis of the targeted tumor(s). The potential advantages of the smaller beads are deeper penetration into the tumor bed, while avoiding premature proximal occlusion of vessels feeding the tumor, and more consistent dosing. Response to therapy will be evaluated monthly by clinic visits and blood tests (to include assessment of liver function and tumor markers) and by imaging (usually MRIs) every 1-2 months. Patients will be on study for 6 months after which they will be exited from the study and followed for survival. Once exited from the study they will continue to be eligible to receive DEBIRI, should it be recommended.

Official Title
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Irinotecan -Eluting LC Bead-M1 (DEBIRI-M1) for Patients With Liver Metastases From Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: DEBIRI
* Device: LC Bead M1
* Procedure: TACE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Patients with a diagnosis of colorectal cancer with hepatic metastases who have failed or are intolerant to at least one systemic chemotherapy or liver directed therapy. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at study entry. The patient is age 18 years or older. The patient has a life expectancy of >12 weeks. Patients with liver dominant disease defined as >/=75% tumor body burden confined to the liver Less than 60% liver tumor replacement At least one month has elapsed since most recent prior cancer therapy with the following exception: -Chemotherapy (excluding irinotecan based regimens) may continue if there is evidence of hepatic progression on treatment providing there is no change in the therapy in the 1 month prior to DEBIRI-TACE treatment and any immediate chemotherapeutic toxicity that will complicate DEBIRI-TACE is resolved. In this case, the chemotherapy may continue because it is continuing to control the extrahepatic disease. The patient has measurable disease that will be directly treated with intrahepatic therapy (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Patients with at least one measurable liver metastases> 2 cm. Patients with patent main portal vein The patient has adequate hematologic function as defined by the following criteria: -An absolute neutrophil count (ANC) >/= 1500/mL, Hemoglobin >/= 9.5 g/dL, and a Platelet count >/=75,000/mL, INR </=1.3 prior to receiving DEBIRI-TACE. The patient has adequate hepatic function, as defined by the following criteria: -Total bilirubin</= 2.0 mg/dL, Aspartate transaminase (AST) and alanine transaminase (ALT) </= 5 x the upper limit of normal (ULN), Albumin >2. The patient has adequate renal function, as defined by the following criteria: -Serum creatinine</=2.0. The patient has a baseline international normalized ratio (INR)<1.5. The patient, if a woman of childbearing potential, has a negative pregnancy test. The patient is able to give written informed consent. The patient is willing and able to comply with study procedures, scheduled visits, and treatment plans. Exclusion Criteria: The patient has a history of another primary cancer (ie, a primary cancer not associated with the patient's current liver tumor), with the exception of (a) curatively resected nonmelanomatous skin cancer; (b) curatively treated cervical carcinoma in situ; or (c) other primary solid tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years prior to enrollment (date of informed consent). 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) Any patient eligible for curative treatment (i.e. resection or radiofrequency ablation) Patients' whose only measurable disease is within an area of the liver previously subject to radiotherapy 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) Marco-shunting noted on the hepatic angiogram. The patient has untreatable bleeding diathesis. The patient has complete main portal vein thrombosis with reversal of flow. The patient has evidence of clinically significant peripheral vascular disease. The patient has brain metastases The patient has clinically significant or symptomatic extrahepatic disease, for example, an uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection requiring parenteral antibiotics Symptomatic congestive heart failure (class II to IV of the New York Heart Association classification for heart disease) Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months Uncontrolled hypertension (systolic blood pressure>150 mmHg, diastolic blood pressure>90 mmHg, found on 2 consecutive measurements separated by a 1-week period despite adequate medical support) Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [NCI-CTCAE Grade 3] or asymptomatic sustained ventricular tachycardia) The patient is pregnant or breast-feeding. Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements There is evidence of substance abuse or medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results The patient is allergic to contrast media that cannot be readily prevented with premedication or managed. Other significant medical or surgical condition, or any medication or treatment, that would place the patient at undue risk and that would preclude the safe use of chemoembolization or would interfere with study participation The patient has peritoneal disease or ascites (greater than trace on imaging).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DEBIRI<br> | Drug: DEBIRI<br>* Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extracted from the tree Camptotheca acuminata. Irinotecan hydrochloride trihydrate is a pale yellow to yellow crystalline powder, it is mixed in DC Beads and injected in the tumor.<br>Device: LC Bead M1<br>* The LC Bead M1, loaded with irinotecan (DEBIRI-M1) to treat patients with hepatic metastases from colorectal cancer.<br>Procedure: TACE<br>* TACE a minimally invasive procedure performed to restrict a tumor's blood supply.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of DEBIRI-M1 Procedure as a Measure of Feasibility (Percentage of Successful Treatments) | Feasibility is defined as achieving an acceptable level of technical success in the use of DEBIRI beads treating hepatic metastases in patients with colorectal cancer. | 6 months | 
| Safety, Defined as Demonstrating Tolerable Device-related Toxicity Profile in the Use of DEBIRI Beads Used to Treat Hepatic Metastases in Patients With Colorectal Cancer | Toxicities assessed as being at least possibly related will be recorded including system organ class, subclass, grade, frequency and time interval from DEBIRI-M1. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Tumor Response by RECIST | Efficacy as assessed by radiographic tumor response using the RECIST criteria at baseline and at 6-week imaging following TACE treatments. Complete Response (CR): Disappearance of all lesions targeted by DEBIRI-M1 Partial Response (PR): At least 30% decrease in sum of longest diameter (LD) of lesions targeted by DEBIRI-M1, taking as reference the baseline sum LD Progressive Disease (PD): At least 20% increase in sum of the LD Of lesions targeted by DEBIRI-M1, taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, of lesions targeted by DEBIRI-M1, taking as reference the smallest sum LD since treatment started | 24 weeks | 
| Efficacy - Tumor Response by mRECIST | Efficacy as assessed by radiographic tumor response using modified RECIST (mRECIST) criteria at baseline and at 6-week imaging following TACE treatments. Complete Response (CR): Disappearance of any intratumoral arterial enhancement in all target lesions Partial Response (PR): At least 30% decrease in the sum of diameters of viable target lesions, taking as reference the baseline sum of the diameters of target lesions Progressive Disease (PD): At least 20% increase in sum of diameters of viable target lesions, taking as reference the smallest sum of diameters of viable target lesions since treatment started. Stable Disease (SD): Any cases that do not qualify for either PR or PD. | 24 weeks | 
| Efficacy -Tumor Response by European Association for the Study of the Liver (EASL) Criteria | Efficacy as assessed by radiographic tumor response using EASL amendment at baseline and at 6-week imaging following TACE treatments. Complete Response (CR): Achieving 100% tumor necrosis of lesions targeted by DEBIRI-M1. Baseline degree of tumor enhancement used as a reference. Partial Response (PR): Demonstrating greater than 50% tumor necrosis in lesions targeted by DEBIRI-M1. Stable Disease (SD): Not meeting requirements for CR or PR and not demonstrating evidence of progression of lesions targeted by DEBIRI-M1. Progressive Disease (PD): Reappearance of or increased tumor enhancement greater than 25% in lesions previously targeted by DEBIRI-M1. | 24 weeks | 
| Efficacy - Tumor Response by World Health Organization (WHO) Criteria | Efficacy as assessed by radiographic tumor response using WHO criteria at baseline and at 6-week imaging following TACE treatments. Complete Response (CR): No lesions detected for at least 4 weeks. Partial Response (PR): 50% or greater decrease in the sum of the products of diameters Stable Disease (SD): Cases that do not fit the criteria of PR or PD. Progressive Disease (PD): 25% or greater increase in the sum of the products of diameters in one or more lesions; or new lesions | 24 weeks | 
| Number of Participants With Change in Carcinoembryonic Antigen (CEA) | CEA measurements pre- and post- DEBIRI treatment will be recorded to ascertain if it is predictive of survival. | 6 weeks | 
| Median Overall Survival | Median overall survival from start of therapy (DEBIRI #1) until death (or date of censor). | Up to 26 months | 
| One-year Survival Percentage | Percentage of study patients surviving after one year from initial treatment analyzed with Kaplan-Meier curve. | 1 year |