Ignite Creation Date:
2024-05-06 @ 8:16 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06313203
Status:
RECRUITING
Last Update Posted:
2024-03-15
First Post:
2024-02-27
Brief Title:
HAI-Floxuridine or SIRT Combined With Gemox For Patients With Intra-Hepatic Cholangiocarcinoma Not Amenable to Resection TOMCAT
Sponsor:
Oslo University Hospital
Organization:
Oslo University Hospital
Study Overview
Official Title:
Trans-arterial Treatment of Patients With Intra-hepatic Cholangiocarcinoma Not Amenable to Resection TOMCAT
Status:
RECRUITING
Status Verified Date:
2024-03
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:
TOMCAT
Brief Summary:
Patients with intrahepatic cholangiocarcinoma IHC have relatively aggressive tumors and the prognosis for most of these patients is dismal Surgery is the only option that can offer potential cure but only an estimated 20-25 are amenable to resection Down-staging conventional chemotherapy has a relatively low response rate 50 Patients will be included into the respective treatment arms based on their tumour characteristics and disease stage but also based on their abilitypreferences as HAI-FUDRDEX requires going to Oslo every fortnight for the duration of the treatment and SIRT has some limitations regarding tumour distribution
Data from the MSKCC has suggested a clinically relevant benefit from adding intrahepatic chemotherapy to systemic therapy HAI-FUDRDEX is not approved in Norway and can only be evaluated in a protocolized trial Given the risk of distant disease progression with IHC the addition of conventional systemic chemotherapy makes good clinical sense and data from MSKCC supports this approach SIRT is another modality also applied trans-arterially and directly into the tumour This treatment is approved in Norway and available in Bergen and in Oslo It is far less cumbersome to deliver and maintain than HAI-FUDRDEX The efficacy and safety of the two treatment groups HAI-FUDRDEX and SIRT will be compared in a parallel cohort non-randomized design
Data from the MSKCC has suggested a clinically relevant benefit from adding intrahepatic chemotherapy to systemic therapy HAI-FUDRDEX is not approved in Norway and can only be evaluated in a protocolized trial Given the risk of distant disease progression with IHC the addition of conventional systemic chemotherapy makes good clinical sense and data from MSKCC supports this approach SIRT is another modality also applied trans-arterially and directly into the tumour This treatment is approved in Norway and available in Bergen and in Oslo It is far less cumbersome to deliver and maintain than HAI-FUDRDEX The efficacy and safety of the two treatment groups HAI-FUDRDEX and SIRT will be compared in a parallel cohort non-randomized design
Detailed Description:
This is a parallel twin cohort study aiming to assess the efficacy and safety of selective internal radiation therapy SIRT and hepatic artery infusion HAI with floxuridine FUDR and dexamethasone DEX in combination with modern systemic chemotherapy The study groups will consist of patients with intrahepatic cholangiocarcinoma IHC not amenable to surgical resection
Thus for many patients with IHC effective treatment options are limited Liver-directed hepatic arterial chemotherapy delivered through a surgically implanted HAI pump has been evaluated in several small series and appears to have greater efficacy than systemic therapy alone Although used predominantly in patients with hepatic colorectal metastases HAI chemotherapy has shown efficacy in patients with primary liver cancer HAI-FUDRDEX is not approved in Norway nor the EU but is used in an ongoing RCT at Oslo University Hospital for the treatment of colorectal cancer liver metastases CRLM Excalibur
Based on the tumor characteristics and tumor stage as well as the patients ability to undergo HAI-FUDRDEX treatment we will divide patients who are not amenable to upfront resection but who are potentially curable into two down-staging treatment groups systemic chemotherapy in combination with either SIRT or HAI with FUDRDEX If allocated to SIRT a standard work-up is performed in Oslo with SIRT being performed at the same site 1-3 weeks later
Trans-arterial treatment modalities If allocated to HAI-FUDRDEX a laparotomy is scheduled within three weeks from inclusion Upon laparotomy hilar lymph nodes are cleared completely and cholecystectomy is performed Placement of The Tricumed IP2000V pump and catheter will be as per current routine The patient is expected to stay at the hospital ward for 3-6 days after the pump is implanted During this time they will undergo a standard control of catheter patency and absence of any collateral which is performed by direct angiography and isotope scanning 3-5 days post surgery
The Tricumed IP2000V pump is used outside its approved indication and experience is limited to other clinical trials using the HAI pump for administration of FUDR The Tricumed IP2000V pump is a constant flow implantable infusion pump intended to store and slowly deliver FUDRDEX intrahepatically The infusion pump is contoured with smooth radius to increase the comfort for patients It contains a fluid reservoir in the form of a titanium bellow that is pressurized by n-butane at constant pressure The n-butane is in phase change between a liquid and a vapor and at body temperature of 37 C provides a constant pressure of 25 bar The body temperature of the patient provides the system with energy This drive system provides the implantable infusion pump with an inexhaustible source of energy The drug therapy is therefore delivered at a substantially constant rate over the whole refill interval Through use of a gaseous drive medium arduous warming up of the implantable infusion pump is no longer necessary before implantation
Surgical complications related to HAI pump placement are uncommon 10 but include hepatic artery thrombosis pump pocket infection and arterial hemorrhage at the site of arterial catheter insertion Prior to the first administration of HAI-FUDRDEX an additional technetium-99-labeled macro aggregated albumin nuclear medicine scan and a CT angiography are performed to confirm bilobar hepatic perfusion and rule out extrahepatic perfusion A total of 5-10 ml contrast agent will be infused with a negligible effect on renal function which is additional to the standard of care HAI-chemotherapy toxicities include ulcer disease and biliary sclerosis which can both be largely avoided by imaging prior to treatment and monitoring of liver tests and dosages adjustments if needed Systemic side effects with HAI chemotherapy of FUDR are rare 1
Hepatic Artery Infusion with Floxuridine and Dexamethasone HAI-FUDRDEX Treatment will be provided in 28-day cycles The Hepatic Artery infusion is dosed with 012 mgkg floxuridine together with 35000 U of heparin 25 mg of dexamethasone and enough normal saline for a total volume of 35 ml This is to be delivered as a 14-day continuous infusion through the pump For patients who are more than 25 above ideal body weight the actual dose of floxuridine is calculated by using a weight that averages the patients actual weight and their ideal weight HAI-FUDRDEX is provided at Day 1 of each cycle and the remaining FUDR in the pump is emptied at Day 15 and then re-filled with 35000 units of heparin in normal saline qs 35 ml and infused over the next 14 days
The patients reference value is defined as the value obtained on the first day of the most recent FUDR dose Variations within hospital reference value range shall not prompt any dose adjustments Bilirubin alkaline phosphatase or AST increases outside of hospital reference value range may necessitate FUDR dose modification To determine if a FUDR dose modification is necessary in these cases the patient reference value is compared to either the value obtained on the day the pump was emptied eg day 14 or the value obtained on the day of planned pump filling eg day 28 whichever is higher Percentages listed under FUDR Dose refer to percentage of last dose of FUDR administered
If patient develops a total bilirubin 50 μmolL the pump should be emptied and dexamethasone 25 mg plus heparin 35000 units and saline 35 ml placed in the pump for 14 days Once there is no longer evidence of toxicity the dexamethasone dose should be tapered in increments of 5 mg every 14 days Tapering will continue unless enzymes increase FUDR should be permanently discontinued unless the patient responded previously and there is evidence of disease progression increasing CEA worsening CT scan worsening clinical status while off therapy AND bilirubin has returned to 26 μmolL In this case FUDR can be restarted as follows use 25 of the last FUDR dose given with dexamethasone heparin and saline in the pump for 7 days Pump should be emptied after 7 days and patients given a 3-week rest period This treatment and treatment schedule should continue as long as bilirubin remains 26 μmolL and liver enzyme values do not increase
Epigastric pain unresponsive to oral H2 blocker use is suggestive of gastroduodenal irritation or ulcer Severe pain should prompt workup with an upper gastrointestinal endoscopy Serum amylase should be checked along with the routine blood screening profile creatinine and CBC in patients with abdominal pain If an ulcer or gastroduodenitis is documented therapy should be held for one month to allow healing If abdominal pain is severe the pump should be emptied of FUDR until results of workup are available
If the physician feels the patient cannot tolerate systemic therapy it can be held for 1-2 weeks If the patient has elevated liver function tests systemic therapy can be held and dexamethason can be placed in the pump with heparin saline at the discretion of the Principal Investigator
Systemic chemotherapy is administered at the patients local hospital some days following pump re-fill approximately at Day 2-3 and 16-17 of each cycle with the exception of Day 3 Cycle 1 if patient will receive HAI-FUDRDEX The Oncologist at the patients local hospital will decide the type and dosage of the patients systemic therapy
At Day 1 and Day 15 of each cycle a brief physical examination is conducted ECOG score obtained vital signs are measured adverse events adverse device effects and toxicity assessments are made and blood sampling for safety laboratory variables are taken In addition weight in kg is measured at Day 1
Selective Internal Radiation Therapy SIRT Selective Internal Radiation Therapy SIRT also named trans-arterial radio-embolization TARE is approved in Norway however used in a limited degree Recent research on hepatocellular carcinoma has shown the importance of personalized dosimetry to obtain high tumour radiation dose while limiting the dose to surrounding liver tissue yielding improved response and survival Dosisphere study it is likely that these findings can be applied also to cholangiocarcinoma
Radioactive Yttrium 90 Y-90 labeled particles are injected selectively into the hepatic artery branches that are feeding arteries of the tumours Y-90 is a β-emitter with a half-life of 64 hours and tissue penetration of 2-10 mm This allows for a high radiation dose in the liver lesion while limiting systemic side effects
Actual treatment will be preceded by a work-up procedure mapping the tumors and the arterial anatomy and flow Based on the distribution of 99Tch-MAA injected into the designated feeders on Spect-CT any lung shunt will be quantified and a treatment plan established in close collaboration with specialists in nuclear medicine and radiation physicists The aim will be a tumor dose of at least 200 Gy liver tissue to be ablated should receive at least 150 Gy The dose to the lung may not exceed 30 Gy while the dose to non-tumorous liver should be kept below 40 Gy In the setting of radiation lobectomy treating tumors while also stimulating liver parenchyma growth this threshold will be higher Tumor characteristics such as number size and hypervascularity all influence dose delivery
Also underlying liver disease will need to be taken into account during dose planning
SIRT will be given at Day 1 in Cycle 1 Initiation of systemic chemotherapy will not take place until two weeks post-SIRT so the first dose of systemic chemotherapy will be given on Cycle 1 Day 15 and then every 2 weeks thereafter Dexamethasone will be provided preoperatively Patients who experience significant nausea following SIRT may be treated with po methylprednisolone for up to one week following SIRT
Patients who have response RECIST 11 on SIRT at 6 months following treatment initiation and then recur or progress in a manner that would have made them eligible for SIRT per inclusion criteria see above can be assessed for re-treatment with SIRT
CT chest abdomen and pelvis blood samples for efficacy evaluation CA 19-9 and CEA and Quality of Life Questionnaires EORTC QLQ-C30 and EQ-5D-5L will be taken every 8 weeks Day 1 of odd numbered cycles
Re-assessments for possible resection or treatment modification will be performed every 8 weeks at regional MDT-meetings
Treatment will continue until death or tumour progression Resected patients will be followed until death or recurrence or at least for three years if no recurrence
Data for patients who are amenable to upfront resection and patients with non-livernon-liver hilum metastatic disease will be retrieved from the UNICORN cohort a national cohort study in establishment which will include all cholangiocarcinoma patients independent of treatment as comparison groups
Overall risk-benefit conclusion For the applicable group of patients few if any treatment options are remaining and the benefits are thus considered to outweigh the risks
Thus for many patients with IHC effective treatment options are limited Liver-directed hepatic arterial chemotherapy delivered through a surgically implanted HAI pump has been evaluated in several small series and appears to have greater efficacy than systemic therapy alone Although used predominantly in patients with hepatic colorectal metastases HAI chemotherapy has shown efficacy in patients with primary liver cancer HAI-FUDRDEX is not approved in Norway nor the EU but is used in an ongoing RCT at Oslo University Hospital for the treatment of colorectal cancer liver metastases CRLM Excalibur
Based on the tumor characteristics and tumor stage as well as the patients ability to undergo HAI-FUDRDEX treatment we will divide patients who are not amenable to upfront resection but who are potentially curable into two down-staging treatment groups systemic chemotherapy in combination with either SIRT or HAI with FUDRDEX If allocated to SIRT a standard work-up is performed in Oslo with SIRT being performed at the same site 1-3 weeks later
Trans-arterial treatment modalities If allocated to HAI-FUDRDEX a laparotomy is scheduled within three weeks from inclusion Upon laparotomy hilar lymph nodes are cleared completely and cholecystectomy is performed Placement of The Tricumed IP2000V pump and catheter will be as per current routine The patient is expected to stay at the hospital ward for 3-6 days after the pump is implanted During this time they will undergo a standard control of catheter patency and absence of any collateral which is performed by direct angiography and isotope scanning 3-5 days post surgery
The Tricumed IP2000V pump is used outside its approved indication and experience is limited to other clinical trials using the HAI pump for administration of FUDR The Tricumed IP2000V pump is a constant flow implantable infusion pump intended to store and slowly deliver FUDRDEX intrahepatically The infusion pump is contoured with smooth radius to increase the comfort for patients It contains a fluid reservoir in the form of a titanium bellow that is pressurized by n-butane at constant pressure The n-butane is in phase change between a liquid and a vapor and at body temperature of 37 C provides a constant pressure of 25 bar The body temperature of the patient provides the system with energy This drive system provides the implantable infusion pump with an inexhaustible source of energy The drug therapy is therefore delivered at a substantially constant rate over the whole refill interval Through use of a gaseous drive medium arduous warming up of the implantable infusion pump is no longer necessary before implantation
Surgical complications related to HAI pump placement are uncommon 10 but include hepatic artery thrombosis pump pocket infection and arterial hemorrhage at the site of arterial catheter insertion Prior to the first administration of HAI-FUDRDEX an additional technetium-99-labeled macro aggregated albumin nuclear medicine scan and a CT angiography are performed to confirm bilobar hepatic perfusion and rule out extrahepatic perfusion A total of 5-10 ml contrast agent will be infused with a negligible effect on renal function which is additional to the standard of care HAI-chemotherapy toxicities include ulcer disease and biliary sclerosis which can both be largely avoided by imaging prior to treatment and monitoring of liver tests and dosages adjustments if needed Systemic side effects with HAI chemotherapy of FUDR are rare 1
Hepatic Artery Infusion with Floxuridine and Dexamethasone HAI-FUDRDEX Treatment will be provided in 28-day cycles The Hepatic Artery infusion is dosed with 012 mgkg floxuridine together with 35000 U of heparin 25 mg of dexamethasone and enough normal saline for a total volume of 35 ml This is to be delivered as a 14-day continuous infusion through the pump For patients who are more than 25 above ideal body weight the actual dose of floxuridine is calculated by using a weight that averages the patients actual weight and their ideal weight HAI-FUDRDEX is provided at Day 1 of each cycle and the remaining FUDR in the pump is emptied at Day 15 and then re-filled with 35000 units of heparin in normal saline qs 35 ml and infused over the next 14 days
The patients reference value is defined as the value obtained on the first day of the most recent FUDR dose Variations within hospital reference value range shall not prompt any dose adjustments Bilirubin alkaline phosphatase or AST increases outside of hospital reference value range may necessitate FUDR dose modification To determine if a FUDR dose modification is necessary in these cases the patient reference value is compared to either the value obtained on the day the pump was emptied eg day 14 or the value obtained on the day of planned pump filling eg day 28 whichever is higher Percentages listed under FUDR Dose refer to percentage of last dose of FUDR administered
If patient develops a total bilirubin 50 μmolL the pump should be emptied and dexamethasone 25 mg plus heparin 35000 units and saline 35 ml placed in the pump for 14 days Once there is no longer evidence of toxicity the dexamethasone dose should be tapered in increments of 5 mg every 14 days Tapering will continue unless enzymes increase FUDR should be permanently discontinued unless the patient responded previously and there is evidence of disease progression increasing CEA worsening CT scan worsening clinical status while off therapy AND bilirubin has returned to 26 μmolL In this case FUDR can be restarted as follows use 25 of the last FUDR dose given with dexamethasone heparin and saline in the pump for 7 days Pump should be emptied after 7 days and patients given a 3-week rest period This treatment and treatment schedule should continue as long as bilirubin remains 26 μmolL and liver enzyme values do not increase
Epigastric pain unresponsive to oral H2 blocker use is suggestive of gastroduodenal irritation or ulcer Severe pain should prompt workup with an upper gastrointestinal endoscopy Serum amylase should be checked along with the routine blood screening profile creatinine and CBC in patients with abdominal pain If an ulcer or gastroduodenitis is documented therapy should be held for one month to allow healing If abdominal pain is severe the pump should be emptied of FUDR until results of workup are available
If the physician feels the patient cannot tolerate systemic therapy it can be held for 1-2 weeks If the patient has elevated liver function tests systemic therapy can be held and dexamethason can be placed in the pump with heparin saline at the discretion of the Principal Investigator
Systemic chemotherapy is administered at the patients local hospital some days following pump re-fill approximately at Day 2-3 and 16-17 of each cycle with the exception of Day 3 Cycle 1 if patient will receive HAI-FUDRDEX The Oncologist at the patients local hospital will decide the type and dosage of the patients systemic therapy
At Day 1 and Day 15 of each cycle a brief physical examination is conducted ECOG score obtained vital signs are measured adverse events adverse device effects and toxicity assessments are made and blood sampling for safety laboratory variables are taken In addition weight in kg is measured at Day 1
Selective Internal Radiation Therapy SIRT Selective Internal Radiation Therapy SIRT also named trans-arterial radio-embolization TARE is approved in Norway however used in a limited degree Recent research on hepatocellular carcinoma has shown the importance of personalized dosimetry to obtain high tumour radiation dose while limiting the dose to surrounding liver tissue yielding improved response and survival Dosisphere study it is likely that these findings can be applied also to cholangiocarcinoma
Radioactive Yttrium 90 Y-90 labeled particles are injected selectively into the hepatic artery branches that are feeding arteries of the tumours Y-90 is a β-emitter with a half-life of 64 hours and tissue penetration of 2-10 mm This allows for a high radiation dose in the liver lesion while limiting systemic side effects
Actual treatment will be preceded by a work-up procedure mapping the tumors and the arterial anatomy and flow Based on the distribution of 99Tch-MAA injected into the designated feeders on Spect-CT any lung shunt will be quantified and a treatment plan established in close collaboration with specialists in nuclear medicine and radiation physicists The aim will be a tumor dose of at least 200 Gy liver tissue to be ablated should receive at least 150 Gy The dose to the lung may not exceed 30 Gy while the dose to non-tumorous liver should be kept below 40 Gy In the setting of radiation lobectomy treating tumors while also stimulating liver parenchyma growth this threshold will be higher Tumor characteristics such as number size and hypervascularity all influence dose delivery
Also underlying liver disease will need to be taken into account during dose planning
SIRT will be given at Day 1 in Cycle 1 Initiation of systemic chemotherapy will not take place until two weeks post-SIRT so the first dose of systemic chemotherapy will be given on Cycle 1 Day 15 and then every 2 weeks thereafter Dexamethasone will be provided preoperatively Patients who experience significant nausea following SIRT may be treated with po methylprednisolone for up to one week following SIRT
Patients who have response RECIST 11 on SIRT at 6 months following treatment initiation and then recur or progress in a manner that would have made them eligible for SIRT per inclusion criteria see above can be assessed for re-treatment with SIRT
CT chest abdomen and pelvis blood samples for efficacy evaluation CA 19-9 and CEA and Quality of Life Questionnaires EORTC QLQ-C30 and EQ-5D-5L will be taken every 8 weeks Day 1 of odd numbered cycles
Re-assessments for possible resection or treatment modification will be performed every 8 weeks at regional MDT-meetings
Treatment will continue until death or tumour progression Resected patients will be followed until death or recurrence or at least for three years if no recurrence
Data for patients who are amenable to upfront resection and patients with non-livernon-liver hilum metastatic disease will be retrieved from the UNICORN cohort a national cohort study in establishment which will include all cholangiocarcinoma patients independent of treatment as comparison groups
Overall risk-benefit conclusion For the applicable group of patients few if any treatment options are remaining and the benefits are thus considered to outweigh the risks
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None