Microparticle Enhanced Cytotoxic Transarterial Embolization Therapy

Microparticle Enhanced Cytotoxic Transarterial Embolization Therapy: A Pilot Study of Irinotecan in the Treatment of Metastatic Colorectal Carcinoma (mCRC) by Embozene TANDEM™ Drug-Eluting Microspheres Embolization

The purpose of this study is to determine safety and local tumor control of Embozene TANDEM Microspheres (40um TANDEM) loaded with Irinotecan to treat metastatic colorectal carcinoma (mCRC).

Colon or rectal carcinoma that has spread to the liver is considered to be metastatic and is a Stage IV cancer. If the metastasized tumor is unresectable, the only current treatment is chemotherapy. Transarterial Chemoembolization (TACE) is considered as a palliative treatment in advanced metastatic colorectal carcinoma (mCRC), with the potential of local tumor control. TACE has evolved in the past 8 years to include drug-delivery devices that can target and deliver drugs from small microparticles (DEB-TACE). Superselective DEB-TACE has the potential to penetrate deeper into the tumor's vasculature to reach peripheral growing points. Loading these microparticles with a cytotoxic drug may improve the level of local tumor control.

The MIRACLE III study is a controlled, pilot, single center (Italy) study on 18 subjects with pretreated non-resectable mCRC.

Inclusion Criteria:

• Male or Female, age >18 yrs who have histologically confirmed adenocarcinoma of the colon or rectum (Stage IV)

• Presence of metastatic disease with liver as dominant disease-site defined as >80% tumor body burden confined to liver; less than 60% liver tumor replacement.

• Subject is competent and willing to provide written informed consent in order to participate in the study.

• Eastern Cooperative Oncology Group (ECOG) performance status is 0-1 or Child-Pugh classification is A or B7.

• Multinodular or single nodular tumor 4 cm, patients with bilobar disease who can be treated superselectively in a single session or both lobes able to be treated within 3 weeks. Patient must have at least one tumor lesion that meets the following criteria: lesion can be accurately measured in at least one dimension according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.

• Pretreatment with two or more lines of chemotherapy containing Fluorouracil (5-FU) or analogue, oxaliplatin, irinotecan ± bevacizumab ±epidermal growth factor receptor (EGFR)-inhibitors, if indicated, for metastatic disease.

• No invasion in the blood vessel (hepatic portal, hepatic vein) or bile duct by the computerized axial tomography (CT) or Magnetic Resonance (MR) Imaging.

• Proper blood, liver, renal, heart function: testing result within 2 weeks from registry of this study as follows:

  1. White Blood Cell (WBC) >3,000 cells/mm3
  2. Absolute neutrophil count ≥1500/mm3
  3. International Normalized Ratio (INR) <2.0
  4. Partial Thromboplastin Time (PTT) <40 sec
  5. Platelet count >50,000/mm3
  6. Blood bilirubin <3.0 mg/dL
  7. Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) is within 5 times of normal range of each organ
  8. Serum creatinine <1.5 mg/dL
  9. Hemoglobin >8.0 g/dL
  10. Alkaline phosphatase <630 IU/L
  11. No unstable coronary artery disease or recent Myocardial Infarction(MI)
  12. Normal electrocardiogram (ECG) with QT interval <480 msec within the previous 12 months
  13. No current infections requiring antibiotic therapy
  14. Not on anticoagulation or suffering from a known bleeding disorder.

• Measureable disease per mRECIST.

• Expected survival more than 3 months

Exclusion Criteria:

• ECOG performance status >2; or Child-Pugh class>11 points or more, or American Society of Anaesthesiologists' (ASA) class 5 .

• Bilirubin levels >3 mg/dL

• mCRC within the large vessel or biliary duct invasion, diffuse hepatocellular carcinoma (HCC) or extrahepatic spread.

• Patients in which any of the following are contraindicated or present:

  1. The use of irinotecan
  2. MRI or CT scans
  3. Hepatic embolization procedures
  4. WBC <3000 cells/mm3
  5. neutrophil <1500 cells/mm3
  6. Cardiac ejection fraction <50% assessed by isotopic ventriculography, echocardiography or MRI
  7. Elevated serum creatinine ≥ 2.5 mg/dL
  8. Impaired clotting test (platelet count < 50,000/mm3, PT-INR >2.0
  9. AST and/or ALT >5x upper limit of normal (ULN), when greater >250 U/I
  10. Known hepatofugal blood flow.
  11. Arterio-venous shunt
  12. Arterio-portal shunt
  13. Main stem portal vein occlusion

• Women who are pregnant or nursing

• Allergy to iodinated contrast used for angiography

• Tumour burden of more than 50% of liver volume (Tumor volume by be smaller e.g. ≤30%)

• Patients with active bacterial, viral (HIV), or fungal infection.

• Other malignancies

• Any co-morbid disease or condition or event that, in the investigator's judgment, would place the patient a undue risk what would preclude the safe use of DEB-TACE.