Ignite Creation Date:
2024-05-06 @ 8:21 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06356883
Status:
RECRUITING
Last Update Posted:
2024-07-12
First Post:
2024-03-19
Brief Title:
Intraarterial Carboplatin Caelyx vs Intraarterial Carboplatin Etoposide Phosphate for Progressing Glioblastoma
Sponsor:
Université de Sherbrooke
Organization:
Université de Sherbrooke
Study Overview
Official Title:
A Randomized Phase II Study on Intraarterial Carboplatin Combined With Caelyx Compared to Intraarterial Carboplatin Combined With Etoposide Phosphate for Progressing Glioblastoma at First or Second Relapse
Status:
RECRUITING
Status Verified Date:
2024-10
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:
The standard of care for glioblastoma GBM treatment involves maximal resection followed by concomitant radiotherapy and temozolomide Progression-free survival PFS with this treatment is only 69 months and relapse is inevitable At relapse there is no consensus regarding the optimal therapeutic strategy The rationale behind the fact that limited chemotherapy agents are available in the treatment of malignant gliomas is related to the blood-brain barrier BBB which impedes drug entry to the brain Intraarterial IA chemotherapy allows to circumvent this Using IA delivery of carboplatin can produce responses in 70 of patients for a median PFS of 5 months Median survival from study entry was 11 months whereas the overall survival OS 23 months How can the OS and PFS be improved By combining chemotherapeutic agents with different mechanisms of action
Study design In this phase II trial treatment will be offered at relapse Surgery will be performed for cytoreduction if it is warranted followed with a combination IA carboplatin IA Cealyx liposomal doxorubicin or IA carboplatin IA etoposide phosphate Toxicity will be assessed according to the NCIC common toxicity criteria Treatment will consist in either IA carboplatin 400 mgm2 IA Cealyx 30 mgm2 or IA carboplatin 400 mgm2 IA etoposide phosphate 400 mgm2 every 4-6 weeks 1 cycle Up to twelve cycles will be offered
Outcome measurements Tumor response will be evaluated using the RANO criteria by magnetic resonance imaging monthly Primary outcome will PFS and tumor response Secondary outcome will include median OS toxicity quality of life QOL neurocognition NC
Putting together these data will allow to correlate clinical and radiological response to QOL and NC
Study design In this phase II trial treatment will be offered at relapse Surgery will be performed for cytoreduction if it is warranted followed with a combination IA carboplatin IA Cealyx liposomal doxorubicin or IA carboplatin IA etoposide phosphate Toxicity will be assessed according to the NCIC common toxicity criteria Treatment will consist in either IA carboplatin 400 mgm2 IA Cealyx 30 mgm2 or IA carboplatin 400 mgm2 IA etoposide phosphate 400 mgm2 every 4-6 weeks 1 cycle Up to twelve cycles will be offered
Outcome measurements Tumor response will be evaluated using the RANO criteria by magnetic resonance imaging monthly Primary outcome will PFS and tumor response Secondary outcome will include median OS toxicity quality of life QOL neurocognition NC
Putting together these data will allow to correlate clinical and radiological response to QOL and NC
Detailed Description:
BACKGROUND - Glioblastoma GBM is the most common and aggressive primary brain tumour in adults The standard first-line treatment for these tumours features maximized surgery followed by radiation with concomitant and adjuvant temozolomide The overall survival OS and progression-free survival PFS observed in the clinic with this paradigm are only 146 and 6 9 months respectively One of the challenges in the treatment of this neoplasm stems from the severe tumour heterogeneity which translates into unpredictable treatment response As a result newly diagnosed tumours inevitably relapse after the standard first-line treatment which is called the Stupp protocol which combines radiation therapy and oral temozolomide When recurrence occurs if the patients functional status is adequate this will mandate other therapeutic strategies Interestingly results obtained in most studies in this setting have been so marginal that there is literally no recognized optimal second and third line of treatment Admittedly the access to active therapies is greatly limited by the presence of the blood-brain barrier BBB which severely reduces the chemotherapy entry to the CNS
When one realizes the extensiveness of the vascular network supplying the brain it appears obvious that a global delivery strategy via this vascular network as a delivery corridor is credible and legitimate The importance of this vascular system has already been detailed by Bradbury the author claims that the entire network covers an area of 12 m2g of cerebral parenchyma To understand the extensiveness of the cerebral vascularization in a more prosaic way let us just consider that the brain receives about 20 of the total systemic circulation although it weighs less than 3 of the total body weight
The access to a patients cerebral vascular network is technically easy and actually repeatedly performed in the clinic on a regular basis Via a simple puncture to access the femoral artery a catheter can be introduced and navigated intraarterially to reach one of the four major cerebral arteries Once in the target vessel a therapeutic agent can be administered via the catheter that is later withdrawn at the conclusion of the procedure The CIAC allows the construct of a regional chemotherapeutic distribution paradigm within the area irrigated by the targeted vessel
An increase in the local plasma peak concentration of the drug yields a significantly improved AUC concentration of drug according to the time through the first pass effect This consequently translates in an increased local exposure of the target tissue to the therapeutic agent Interestingly as our lab as shown it is also accompanied by a decreased systemic drug distribution hence reducing systemic toxicity and potential side effects Consequently the therapeutic concentration at the targeted tumour cells is increased by a 35 to 5-fold factor This procedure is performed in the angiographic suite under local anesthesia and typically lasts around 45 minutes
The IA procedure is a very safe procedure Indeed this procedure has been used at our institution for over 15 years using various chemotherapeutic agents and thus have precise statistics on the risks and complications Indeed 722 different patients have been treated adding up to 3600 procedures and have compiled the following events During the MRI that followed the IA infusion 66 complications were identified 184 27 of which were associated to symptoms 075 During the infusion 39 episodes of seizures occurred 108 all of which were successfully controlled with anti-seizure medication Moreover a significant reduction in white red or platelet blood cell count occurred in 52 patients during the treatment phase 72 This study will investigate the efficacy of using combined chemotherapeutic agents described above Our team currently uses intraarterial IA infusion to alleviate the effects of the BBB This delivery strategy was shown to be well tolerated triggered very few discomforts and side effects and significantly improved survival So much so that it is nowadays considered a standard of care for relapsing tumours in our institution
Like cisplatin carboplatin is a molecule made of a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position Unlike the chloride atoms found in cisplatin the ligands in carboplatin are esther functional groups that form a ring structure As such carboplatin is more stable causes less vomiting and is less neurotoxic less ototoxic and less nephrotoxic Carboplatins exact mechanism of action remains unclear However it is well known that carboplatin is activated inside the cell into reactive platinum species These reactive complexes react with DNA bases to create inter- and intrastrand crosslinks which prevent cell division by hindering DNA synthesis
At our institution carboplatin is the primary chemotherapeutic agent for IA infusions and yields positive tumour responses in 70 of patients for a median PFS of 5 months Although interesting there is obviously room for improvement in the care of these patients Hence the current proposal
For patients in which carboplatin fails other chemotherapeutics are chosen arbitrarily from a list of agents available for IA infusion As such our team has successfully treated relapsing GBM patients with IA delivery of methotrexate melphalan etoposide phosphate or Caelyx liposomal doxorubicin At the heart of the present study carboplatin which will be combined with either one of two agents found to be ideally suited in this setting Caelyx liposomal doxorubicin or etoposide phosphate
Doxorubicin is an anthracycline an antineoplastic antibiotic developed from Streptomyces peucetius subsp Cassius It is a very potent antitumour agent and is considered one of the most active antineoplastic drugs developed to date Its effect is produced via different mechanisms DNA binding and cross-linking interference with DNA strand separation inhibition of RNA polymerase inhibition of topoisomerase II formation of free radicals and membrane peroxidation have all been suggested
In vitro studies in malignant glial cell lines have demonstrated that doxorubicin induces a halt in cell growth within 24 hours and results in apoptosis within 48 hours It has been identified as one of the most potent chemotherapeutic drugs against malignant glioma cell lines in vitro However in vivo the use of doxorubicin is limited by its inability to cross the BBB
Doxorubicin is rapidly distributed in the body tissues and binds to plasma protein and cell membranes The clinical application of this agent is unfortunately limited by its dose-related side effects such as cardiotoxicity and myleotoxicity
Caelyx is a chlorhydrate of doxorubicin encapsulated within a pegylated liposome The liposomal formulation of doxorubicin Caelyx exhibits an altered pharmacokinetic profile favouring the use of this drug formulation in brain tumour treatment It has a longer terminal half-life than free doxorubicin and reaches greater concentration in the tumour Because of a decreased uptake by the reticuloendothelial system the drug remains in circulation much longer This seems to be especially true in glioblastoma where it tends to accumulate in significant concentration due to the increase in neovascularisation This has been shown in experimental settings as well as in the clinic Interestingly because of its altered pharmacokinetic properties it also presents a reduced toxicity profile The liposomal formulation of doxorubicin causes less myelosuppression nausea vomiting and alopecia than standard doxorubicin The cardiotoxicity is also reduced
However even with the greater accumulation of the drug in the tumour cells its rate of BBB penetration when administered via IV infusion remains a limiting factor Indeed it is too low to yield a significant concentration accumulation within the tumour site to produce a therapeutic benefit
Etoposide phosphate Etopophos Bristol-Myers Squibb Company Princeton NJ is a water-soluble prodrug of etoposide that is rapidly and completely converted to the parent compound after intravenous dosing The pharmacokinetic profile of either etoposide or etoposide phosphate is identical Toxicity and clinical activity are also the same Since etoposide phosphate is water soluble solutions of up to 20 mgmL can be prepared However in high doses it can only be given as a 5-minute bolus in small volumes and as a continuous infusion Furthermore it is not formulated with polyethylene glycol polysorbate 80 Tween ICI Americas Wilmington DE and ethanol and does not cause acidosis when given at high doses The easier-to-use etoposide phosphate represents an improved formulation of etoposide
Classically etoposide must be diluted prior to use with sodium chloride 09 wv or glucose 5 wv solutions to concentration of 02 mgmL ie 1 ml of concentrate in 100 ml of vehicle up to 04 mgmL ie 2 ml of concentrate in 100 ml of vehicle Evidently this cannot be something considered in a setting of IA administration as the volume administered would be excessive Hence the use of etoposide phosphate for which 100-fold increased concentration can be prepared in a volume accessible for an IA administration 200 cc
STUDY DESIGN - This clinical trial will be an open label randomized phase II study in which intraarterial administration of carboplatin 400 mgm2 combined with Caelyx 30 mgm2 will be compared with intraarterial administration of carboplatin 400 mgm2 combined with etoposide phosphate 400 mgm2 Patients that have failed the standard first line of treatment Stupp protocol and that are diagnosed with recurrent GBM will be randomly distributed to one of the two second-line treatment paradigms using the block randomization method Each recruited patient will undergo maximal resection before beginning treatments Treatment cycles will be administered on a monthly basis until a progression is identified on the magnetic resonance imaging MRI scan or until a total of 12 cycles have been completed The cohort will count 120 patients that will be divided into two groups of 60 patients receiving one of the two chemotherapeutic combinations As to which of the two combinations will be best remains to be determined For that reason data from our latest published clinical trial and patients treated with intraarterial carboplatin at our institution will be used as benchmarks for baseline comparisons OS of 11 months and PFS of 5 months from study entry
AIM - By using carboplatin in combination with Caelyx or etoposide phosphate in the setting of an IA infusion our intention is to optimally deliver carboplatin-based chemotherapy combinations to the brain beyond the BBB and more specifically to the tumour cells
HYPOTHESES - In patients treated with either combination our prediction is that this will lead to an improved tumour response and control rate with minimal impact on the quality of life Our preliminary clinical data seems to support this hypothesis
When one realizes the extensiveness of the vascular network supplying the brain it appears obvious that a global delivery strategy via this vascular network as a delivery corridor is credible and legitimate The importance of this vascular system has already been detailed by Bradbury the author claims that the entire network covers an area of 12 m2g of cerebral parenchyma To understand the extensiveness of the cerebral vascularization in a more prosaic way let us just consider that the brain receives about 20 of the total systemic circulation although it weighs less than 3 of the total body weight
The access to a patients cerebral vascular network is technically easy and actually repeatedly performed in the clinic on a regular basis Via a simple puncture to access the femoral artery a catheter can be introduced and navigated intraarterially to reach one of the four major cerebral arteries Once in the target vessel a therapeutic agent can be administered via the catheter that is later withdrawn at the conclusion of the procedure The CIAC allows the construct of a regional chemotherapeutic distribution paradigm within the area irrigated by the targeted vessel
An increase in the local plasma peak concentration of the drug yields a significantly improved AUC concentration of drug according to the time through the first pass effect This consequently translates in an increased local exposure of the target tissue to the therapeutic agent Interestingly as our lab as shown it is also accompanied by a decreased systemic drug distribution hence reducing systemic toxicity and potential side effects Consequently the therapeutic concentration at the targeted tumour cells is increased by a 35 to 5-fold factor This procedure is performed in the angiographic suite under local anesthesia and typically lasts around 45 minutes
The IA procedure is a very safe procedure Indeed this procedure has been used at our institution for over 15 years using various chemotherapeutic agents and thus have precise statistics on the risks and complications Indeed 722 different patients have been treated adding up to 3600 procedures and have compiled the following events During the MRI that followed the IA infusion 66 complications were identified 184 27 of which were associated to symptoms 075 During the infusion 39 episodes of seizures occurred 108 all of which were successfully controlled with anti-seizure medication Moreover a significant reduction in white red or platelet blood cell count occurred in 52 patients during the treatment phase 72 This study will investigate the efficacy of using combined chemotherapeutic agents described above Our team currently uses intraarterial IA infusion to alleviate the effects of the BBB This delivery strategy was shown to be well tolerated triggered very few discomforts and side effects and significantly improved survival So much so that it is nowadays considered a standard of care for relapsing tumours in our institution
Like cisplatin carboplatin is a molecule made of a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position Unlike the chloride atoms found in cisplatin the ligands in carboplatin are esther functional groups that form a ring structure As such carboplatin is more stable causes less vomiting and is less neurotoxic less ototoxic and less nephrotoxic Carboplatins exact mechanism of action remains unclear However it is well known that carboplatin is activated inside the cell into reactive platinum species These reactive complexes react with DNA bases to create inter- and intrastrand crosslinks which prevent cell division by hindering DNA synthesis
At our institution carboplatin is the primary chemotherapeutic agent for IA infusions and yields positive tumour responses in 70 of patients for a median PFS of 5 months Although interesting there is obviously room for improvement in the care of these patients Hence the current proposal
For patients in which carboplatin fails other chemotherapeutics are chosen arbitrarily from a list of agents available for IA infusion As such our team has successfully treated relapsing GBM patients with IA delivery of methotrexate melphalan etoposide phosphate or Caelyx liposomal doxorubicin At the heart of the present study carboplatin which will be combined with either one of two agents found to be ideally suited in this setting Caelyx liposomal doxorubicin or etoposide phosphate
Doxorubicin is an anthracycline an antineoplastic antibiotic developed from Streptomyces peucetius subsp Cassius It is a very potent antitumour agent and is considered one of the most active antineoplastic drugs developed to date Its effect is produced via different mechanisms DNA binding and cross-linking interference with DNA strand separation inhibition of RNA polymerase inhibition of topoisomerase II formation of free radicals and membrane peroxidation have all been suggested
In vitro studies in malignant glial cell lines have demonstrated that doxorubicin induces a halt in cell growth within 24 hours and results in apoptosis within 48 hours It has been identified as one of the most potent chemotherapeutic drugs against malignant glioma cell lines in vitro However in vivo the use of doxorubicin is limited by its inability to cross the BBB
Doxorubicin is rapidly distributed in the body tissues and binds to plasma protein and cell membranes The clinical application of this agent is unfortunately limited by its dose-related side effects such as cardiotoxicity and myleotoxicity
Caelyx is a chlorhydrate of doxorubicin encapsulated within a pegylated liposome The liposomal formulation of doxorubicin Caelyx exhibits an altered pharmacokinetic profile favouring the use of this drug formulation in brain tumour treatment It has a longer terminal half-life than free doxorubicin and reaches greater concentration in the tumour Because of a decreased uptake by the reticuloendothelial system the drug remains in circulation much longer This seems to be especially true in glioblastoma where it tends to accumulate in significant concentration due to the increase in neovascularisation This has been shown in experimental settings as well as in the clinic Interestingly because of its altered pharmacokinetic properties it also presents a reduced toxicity profile The liposomal formulation of doxorubicin causes less myelosuppression nausea vomiting and alopecia than standard doxorubicin The cardiotoxicity is also reduced
However even with the greater accumulation of the drug in the tumour cells its rate of BBB penetration when administered via IV infusion remains a limiting factor Indeed it is too low to yield a significant concentration accumulation within the tumour site to produce a therapeutic benefit
Etoposide phosphate Etopophos Bristol-Myers Squibb Company Princeton NJ is a water-soluble prodrug of etoposide that is rapidly and completely converted to the parent compound after intravenous dosing The pharmacokinetic profile of either etoposide or etoposide phosphate is identical Toxicity and clinical activity are also the same Since etoposide phosphate is water soluble solutions of up to 20 mgmL can be prepared However in high doses it can only be given as a 5-minute bolus in small volumes and as a continuous infusion Furthermore it is not formulated with polyethylene glycol polysorbate 80 Tween ICI Americas Wilmington DE and ethanol and does not cause acidosis when given at high doses The easier-to-use etoposide phosphate represents an improved formulation of etoposide
Classically etoposide must be diluted prior to use with sodium chloride 09 wv or glucose 5 wv solutions to concentration of 02 mgmL ie 1 ml of concentrate in 100 ml of vehicle up to 04 mgmL ie 2 ml of concentrate in 100 ml of vehicle Evidently this cannot be something considered in a setting of IA administration as the volume administered would be excessive Hence the use of etoposide phosphate for which 100-fold increased concentration can be prepared in a volume accessible for an IA administration 200 cc
STUDY DESIGN - This clinical trial will be an open label randomized phase II study in which intraarterial administration of carboplatin 400 mgm2 combined with Caelyx 30 mgm2 will be compared with intraarterial administration of carboplatin 400 mgm2 combined with etoposide phosphate 400 mgm2 Patients that have failed the standard first line of treatment Stupp protocol and that are diagnosed with recurrent GBM will be randomly distributed to one of the two second-line treatment paradigms using the block randomization method Each recruited patient will undergo maximal resection before beginning treatments Treatment cycles will be administered on a monthly basis until a progression is identified on the magnetic resonance imaging MRI scan or until a total of 12 cycles have been completed The cohort will count 120 patients that will be divided into two groups of 60 patients receiving one of the two chemotherapeutic combinations As to which of the two combinations will be best remains to be determined For that reason data from our latest published clinical trial and patients treated with intraarterial carboplatin at our institution will be used as benchmarks for baseline comparisons OS of 11 months and PFS of 5 months from study entry
AIM - By using carboplatin in combination with Caelyx or etoposide phosphate in the setting of an IA infusion our intention is to optimally deliver carboplatin-based chemotherapy combinations to the brain beyond the BBB and more specifically to the tumour cells
HYPOTHESES - In patients treated with either combination our prediction is that this will lead to an improved tumour response and control rate with minimal impact on the quality of life Our preliminary clinical data seems to support this hypothesis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None