Ignite Creation Date:
2024-05-06 @ 3:42 AM
Last Modification Date:
2024-10-26 @ 11:37 AM
Study NCT ID:
NCT02350400
Status:
COMPLETED
Last Update Posted:
2017-02-14
First Post:
2014-11-26
Brief Title:
Pilot Study to Assess the Safety and Pharmacokinetics of 70-150μm Drug Eluting Beads Loaded With Irinotecan DEBIRI
Sponsor:
Singapore General Hospital
Organization:
Singapore General Hospital
Study Overview
Official Title:
Pilot Study to Assess the Safety and Pharmacokinetics of 70-150μm Drug Eluting Beads Loaded With Irinotecan DEBIRI in the Treatment of Hepatic Colorectal Metastases
Status:
COMPLETED
Status Verified Date:
2017-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 UGT1A128 and UGT1A16 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
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 UGT1A128 and UGT1A16 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
Detailed Description:
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 11 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 physicians discretion should
Liver function tests and bilirubin 5-folds more than the normal values
Absolute neutrophil count of less than 1500 cellsµL
Platelet count of less than 100000µL
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 andor offer patients other treatment modalities eg radiotherapy or further lines of chemotherapy
4Follow 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
5Pharmacokinetics 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 15 mL polypropylene tube and stored at -20C Irinotecan and its metabolites SN-38 and SN-38G will be assayed using LC-MSMS method The purpose of performing pharmacokinetics would be to quantitate the AUC of irinotecan SN-38 and SN-38G in plasma
6Pharmacogenetics Analysis Pharmacogenetic analyses for UGT1A128 and UGT1A16 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 patients identification number date of collection age ethnic group and sex
Unused DNA samples from patients enrolled in the genotyping arm will be stored at -20C for future pharmacogenetic investigations related to irinotecan research Patients will be informed and written consent will be taken from them
8Potential 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
9Adverse events
Using Health Science Authoritys 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 disabilityincapacity or
5 A congenital anomalybirth 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
10Safety 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 patients parameters
All complications and adverse events will be recorded in the CRFs and the patient will be followed up
In the event of any SAEs 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
11Confidentiality 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 patients hospital files either paper or electronic records
Necessary corrections will be entered by the investigator or if appropriate by an authorized member of the investigators 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
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 11 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 physicians discretion should
Liver function tests and bilirubin 5-folds more than the normal values
Absolute neutrophil count of less than 1500 cellsµL
Platelet count of less than 100000µL
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 andor offer patients other treatment modalities eg radiotherapy or further lines of chemotherapy
4Follow 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
5Pharmacokinetics 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 15 mL polypropylene tube and stored at -20C Irinotecan and its metabolites SN-38 and SN-38G will be assayed using LC-MSMS method The purpose of performing pharmacokinetics would be to quantitate the AUC of irinotecan SN-38 and SN-38G in plasma
6Pharmacogenetics Analysis Pharmacogenetic analyses for UGT1A128 and UGT1A16 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 patients identification number date of collection age ethnic group and sex
Unused DNA samples from patients enrolled in the genotyping arm will be stored at -20C for future pharmacogenetic investigations related to irinotecan research Patients will be informed and written consent will be taken from them
8Potential 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
9Adverse events
Using Health Science Authoritys 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 disabilityincapacity or
5 A congenital anomalybirth 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
10Safety 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 patients parameters
All complications and adverse events will be recorded in the CRFs and the patient will be followed up
In the event of any SAEs 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
11Confidentiality 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 patients hospital files either paper or electronic records
Necessary corrections will be entered by the investigator or if appropriate by an authorized member of the investigators 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None