Pilot Study to Assess the Safety and Pharmacokinetics of 70-150μm Drug Eluting Beads Loaded With Irinotecan (DEBIRI).
Pilot Study to Assess the Safety and Pharmacokinetics of 70-150μm Drug Eluting Beads Loaded With Irinotecan (DEBIRI).
Background

 Hepatic metastases of colorectal cancer (MCC) is quite common and is a major source of
 morbidity and mortality. There has been evidence to show that hepatic arterial
 chemoembolisation using DC beads (drug eluting beads, 100-300μm) loaded with irinotecan
 (DEBIRI) showed improved overall survival when compared to systemic therapy (FOLFIRI), but
 being larger they have their limitations.

 New 70-150μm beads are recently available and currently there is limited data concerning its
 use. Safety of these beads have not been tested in local patients.

 Hypothesis / Aim To study the safety and pharmacokinetics of the smaller 70-150μm DEBIRI in a
 pilot study of 5 patients. The smaller 70-150μm beads will be able to deliver a more
 consistent and higher dose to tumoral tissue with a smaller systemic dose. Being smaller and
 less embolic, it will also be better tolerated. Patients will also be genotyped for their
 UGT1A1*28 and UGT1A1*6 polymorphism status as the latter genotypes are associated with
 decreased clearance of irinotecan and SN-38 in Asian patients.

 Methods Single centre, pilot study, prospectively recruiting 5 patients with unilobar
 disease, refractory to systemic chemotherapy

 The primary endpoints:

 1. establish safety and toxicity profile of the irinotecan loaded DEBIRI beads

 2. establish pharmacokinetics and systemic exposure of irinotecan and its active
 metabolite, SN-38.

 The secondary outcome measurements:

 1. the incidence and severity of adverse events, liver function parameters and laboratory
 abnormalities;

 2. response rate,

 3. progression free survival

 4. overall survival

 Clinical Significance

 This treatment modality has the advantage of directly delivering irinotecan to the liver
 metastases from colorectal cancer. This local mode of drug delivery may result in a higher
 intratumoral drug concentration and rapid tumour shrinkage leading to downstaging of the
 hepatic metastatic lesions. These therapeutic outcomes may also downstage patients to hepatic
 resection.
1. Recruitment:

 Suitable potential subjects will be identified, namely those who have failed first or
 second line chemotherapy agents.

 2. Liver biopsy Right before the 1st transarterial chemoembolisation procedure, the liver
 metastases will be biopsied under ultrasound or CT guidance by the IR with a 18G core
 biopsy needle. Tissue will be sent for histological analysis as well as stored for
 molecular studies with NCCS.

 3. Transarterial chemoembolisation procedure (DEBIRI TACE):

 100mg of irinotecan will be loaded into the DEB solution at least 2 hours before the
 procedure by the pharmacy.

 Diagnostic angiography (DSA) will performed under fluoroscopic guidance, most commonly via
 right groin puncture. Using dedicated catheters, arterial supply of the liver and the tumour
 involved segments will be determined. A solution of 75-150 μm DEBIRI mixed with non-ionic
 contrast medium (1:1) will be injected into the artery feeding the metastases.

 For unilobar disease, two treatments will be planned, each of them with a maximum of 100mg
 irinotecan loaded in into the DEB, separated by four weeks. Intravenous fentanyl will be
 administered for procedural pain relief. Post procedural pain relief medications will be
 given as deemed necessary by the physician.

 For bilobar disease, there will be four treatments planned, alternating between the right and
 left lobe, separated by 2 weeks duration, each of them with a maximum of 100mg irinotecan
 loaded into the DEB. Intravenous fentanyl will be administered for the procedural pain
 relief. Post procedural pain relief will be given as deemed necessary by the physician.

 Technical success is defined as delivery of all the DEBIRI or when stasis has been reached in
 the hepatic artery.

 Patients will be expected to stay in the hospital for at least a day for monitoring of
 adverse events, after which they will be followed up in the clinic.

 Procedures will be delayed at the physician's discretion should:

 -  Liver function tests and bilirubin 5-folds more than the normal values

 -  Absolute neutrophil count of less than 1500 cells/µL

 -  Platelet count of less than 100,000/µL

 -  Severe adverse events.

 Should the patient development significant extrahepatic metastases at any time during the
 course of the trial, the referring clinician may choose to stop the trial and/or offer
 patients other treatment modalities e.g. radiotherapy or further lines of chemotherapy.

 4)Follow up:

 Patients will be expected to stay in the hospital for at least a day for monitoring of
 adverse events, after which they will be followed up in the clinic. All patients will be seen
 in the clinical 1 week after each procedure with FBC and LFT determinations being performed.
 They will then be seen in the clinic 1 week prior to their next procedure.

 Patients will be followed up 3 months after the last procedure. Serum drug levels and adverse
 events will be monitored. Imaging response will be determined by modified RECIST criteria.

 A CT scan will be performed 1 month and 3 months after completion of the procedure to
 evaluate treatment response. Tumor response will be determined using modified RECIST criteria
 (7).

 5)Pharmacokinetics of irinotecan Blood samples (3 mL) for pharmacokinetic analyses will be
 collected at the following time points after administration of the first dose on day 1: 0
 minutes (pretreatment blank), 1h, 2h, 4h, 8h and 24h hours postinfusion. Blood will be
 immediately centrifuged at 2000 g for fifteen minutes, and the plasma transferred to a 1.5 mL
 polypropylene tube and stored at -20°C. Irinotecan and its metabolites, SN-38 and SN-38G will
 be assayed using LC-MS/MS method. The purpose of performing pharmacokinetics would be to
 quantitate the AUC of irinotecan, SN-38 and SN-38G in plasma.

 6)Pharmacogenetics Analysis Pharmacogenetic analyses for UGT1A1*28 and UGT1A1*6 will be done
 in all patients prior to administration of irinotecan in accordance with previously published
 studies by our laboratory (6-9). All participating patients will have venous blood samples (3
 mL) drawn for genomic DNA collection in EDTA tubes and labeled with the patient's
 identification number, date of collection, age, ethnic group and sex.

 Unused DNA samples from patients enrolled in the genotyping arm will be stored at -20°C for
 future pharmacogenetic investigations related to irinotecan research. Patients will be
 informed and written consent will be taken from them.

 8)Potential Risks and benefits

 Anticipated benefits:

 1. Reduction in the size of the liver lesions hence prolonging survival

 2. Meeting criteria for liver resection for metastases

 Possible risks:

 Adverse events related to procedure include:

 1. Access site injuries

 2. Hepatic artery injury

 3. Non target embolization resulting in acute cholecystitis, peptic ulcer, pancreatitis
 etc.

 4. Post embolization syndrome, manifested by fever, malaise, right upper quadrant pain,
 nausea, and vomiting

 5. Hepatic abscess and biloma

 6. Biliary strictures

 7. Liver failure

 Adverse events related to irinotecan include:

 1. Diarrhea

 2. Vomiting

 3. Leucopenia

 4. Anemia

 5. Thrombocytopenia

 7. Abdominal pain 8. Fever

 All chemotherapeutic toxicities will be graded according to the National Cancer Institute
 Common Toxicity Criteria (NCI CTC version 3).

 Hematological Dose Limiting Toxicity (DLT) is defined as follows: grade 4 neutropenia of >7
 days duration, neutropenic fever, grade 4 anemia or grade 3-4 thrombocytopenia that occurs
 during the first cycle of treatment.

 9)Adverse events

 Using Health Science Authority's Safety Reporting for Clinical Trials (June 2011), a serious
 adverse event (experience) or reaction is any untoward medical occurrence that at any dose

 1. Results in death

 2. Is life-threatening

 3. Requires inpatient hospitalisation or prolongation of existing hospitalization

 4. Results in persistent or significant disability/incapacity, or

 5. A congenital anomaly/birth defect.

 An adverse event is defined as: Any untoward medical occurrence in a patient or clinical
 investigation subject administered a medicinal product and which does not necessarily have a
 causal relationship with this treatment.

 Adverse events related to procedure include:

 1. Access site injuries

 2. Hepatic artery injury

 3. Non target embolization resulting in acute cholecystitis, peptic ulcer, pancreatitis
 etc.

 4. Post embolization syndrome, manifested by fever, malaise, right upper quadrant pain,
 nausea, and vomiting

 5. Hepatic abscess and biloma

 6. Biliary strictures

 7. Liver failure

 All chemotherapeutic toxicities will be graded according to the National Cancer Institute
 Common Toxicity Criteria (NCI CTC version 3).

 Hematological Dose Limiting Toxicity (DLT) is defined as follows: grade 4 neutropenia of >7
 days duration, neutropenic fever, grade 4 anemia or grade 3-4 thrombocytopenia that occurs
 during the first cycle of treatment.

 Non-hematologic DLT is defined as any grade 3 or grade 4 non-hematologic toxicity that occurs
 during the first cycle of treatment.

 Toxicities will be classified as related to the study drug unless they were attributable to
 either underlying tumour progression, concurrent medical condition or a concomitant
 medication. Any unusual toxicities must be reported to the Principal Investigator.

 10)Safety Monitoring Plan

 Data monitoring

 - The principle and co-investigators.

 Safety monitoring

 -  The medical practitioner performing the procedure will be overall responsible for the
 patient prior to, during and after the intervention.

 -  The monitoring nurse in the recovery area and the circulating nurse during the procedure
 will assist the medical practitioner in recording and monitoring the patient's
 parameters.

 -  All complications and adverse events will be recorded in the CRFs and the patient will
 be followed up.

 In the event of any SAE's regardless of the causality of the event, the investigator will
 notify to the IRB of SingHealth. The reporting timelines are:

 Urgent Reporting: All problems involving local deaths should be reported immediately within
 24 hours after first knowledge by the investigator.

 Expedited Reporting: All other SAE must be reported as soon as possible but not later than 7
 calendar days after first knowledge by the investigator.

 A Data & Safety Monitoring Committee (DSMC) comprising of co-principal investigators from the
 participating centres, will monitor the safety data .

 If the DSMC have any safety concerns, they may make written recommendations to the primary PI
 and the IRB of SingHealth to modify or terminate the study following discussions with the
 primary PI. The final decision on the termination of the study will be made by SGH after
 consulting with IRB and HSA about the safety findings or concerns.

 11)Confidentiality of Data and Patient Records

 Data required according to the protocol will be recorded on the CRFs as soon as possible.

 -  Entries must be made with a ballpoint pen and written legibly. No pencils or correction
 fluids will be used.

 -  Relevant information will be documented into the patient's hospital files (either paper
 or electronic records).

 -  Necessary corrections will be entered by the investigator or, if appropriate, by an
 authorized member of the investigator's staff in the following manner: The wrong entry
 will be crossed out, although it must remain legible, and the correct entry will be
 placed next to it. All corrections will be initialed and dated. For corrections
 concerning adverse events or the primary variable, a reason for any alteration must be
 provided.

 -  Any documents related to the study must be archived at the study site or in a central
 archive. This includes the careful listing of the identities of the patients involved in
 the study. This list and the signed informed consent statements are key documents in the
 files to be stored by the investigator.

 -  Patient (hospital) files will be archived according to local regulations. All documents
 related to the study must be retained until at least 15 years after the end of the
 study. At the end of this period, the investigator is to obtain permission from the
 relevant authorities (IRB) before any documents are destroyed.
Inclusion Criteria:

 1. Metastatic colorectal carcinoma to the liver, both unilobar and bilobar disease

 2. Refractory to 1st or 2nd line systemic chemotherapy. Previous chemotherapy had to be
 discontinued at least 4 weeks prior to study entry

 3. Hepatic disease should be 80% or more of total body tumor burden

 4. Measurable liver tumour burden was of no more than 60% of the total liver volume.

 5. A performance status of 0-2 (WHO criteria).

 6. Age <85 years were required.

 7. Life expectancy of greater than 3 months

 8. Adequate hematologic function (granulocyte count ≥ 1.5 × 109/L, platelet count ≥ 100 ×
 109/L, INR ≤ 1.3 in patients on anticoagulant therapy)Adequate hepatic function (total
 bilirubin ≤ 1.5 x the upper limits of normal [ULN], AST and ALT ≤ 5 x ULN, and
 alkaline phosphatases < 5 x ULN) and,

 9. Adequate renal function (creatinine clearance > 50 mL/min)

 Exclusion Criteria:

 1. Extrahepatic tumor burden of > 20%.

 2. Patients with unilobar disease who are candidates for surgical resection.

 3. Extensive tumor involvement of the liver (>60%)

 4. Poor performance status (>2 WHO criteria)

 5. Significant diseases of cardiac, renal, bone marrow or pulmonary apparatus, central
 nervous system involvement, and uncontrolled infection

 6. Liver function tests and bilirubin 5-folds more than the normal value

 7. History of other cancer except adequately treated in situ carcinoma of the cervix or
 basal or squamous carcinoma of the skin

 8. Absolute neutrophil count of less than 1500 cells/µL

 9. Platelet count of less than 100,000/µL

 10. Significant portal vein thrombosis

 11. Unable to understand nature of study and provide written consent.