Ignite Creation Date:
2024-05-06 @ 8:06 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06258018
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-14
First Post:
2024-01-11
Brief Title:
Niraparib and Temozolomide in Patients Glioblastoma
Sponsor:
Armando Santoro MD
Organization:
Istituto Clinico Humanitas
Study Overview
Official Title:
A Phase I-II Study of Niraparib Plus Temozolomide One Week on One Week Off in Patients With Recurrent Isocitrate Dehydrogenase IDH Wild Type Glioblastoma and IDH Mutant Gliomas
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
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:
ONC-2022-001
Brief Summary:
The study evaluates safety tolerability pharmacokinetics at recommended phase II dose RP2D and preliminary antitumor activity of Niraparib dd-TMZ one week on one week off in patients affected by recurrent GBM IDH wild-type and recurrent IDH mutant WHO grade 2-4 gliomas
The treatment will be administered until progressive disease unacceptable toxicity consent withdrawal lost to follow-up or death
The entire study is expected to last approximately 40 months
The treatment will be administered until progressive disease unacceptable toxicity consent withdrawal lost to follow-up or death
The entire study is expected to last approximately 40 months
Detailed Description:
Diffuse malignant gliomas are the most common central nervous system CNS primary tumours in adults characterized by poor prognosis and few treatment options In the last 15 years standard treatment consisting of surgery adjuvant radiotherapy and temozolomide TMZ-based chemotherapy has remained unchanged New therapeutic approaches are urgently needed
TMZ is a DNA-methylating chemotherapeutic agent with good CNS penetration Its mechanism of action is increased by either gene promoter methylation or consumption of the methylguanine-DNA methyltransferase MGMT an enzyme repairing chemotherapy-induced genome damages
Alternative intensified schedules of TMZ dose-dense TMZ dd-TMZ can give patients an increased total dose of drugs per each cycle progressively consuming MGMT and overcoming resistance of cancer cells to standard first-line schedule They are usually used at disease recurrence with a tolerable safety profile For example a clinical study testing the 7 day on 7 day off schedule showed that MGMT activity in blood mononuclear cells decreased at day 8 and progressively recovered during the week-off This may limit haematological toxicity
The inhibition of Poly ADP-ribose polymerase PARP proteins normally involved in genomic stability may rationally improve TMZ efficacy Switching off PARP molecules can block both base-excision repair BER system and Poly-ADP ribose-ylation of MGMT a key process for its function leading to an amplification in DNA damages In the subset of Isocitrate dehydrogenase IDH 12 mutant gliomas the enzyme leads to 2-hydroxy-glutarate 2HG accumulation in cancer cells This onco-metabolite increases sensitivity to DNA damages by alkylating agents and induces a Breast Cncer geneBRCA-ness phenotype indeed Considering all this the use of PARP inhibitors seems promising even for these patients
When compared to other PARP inhibitors Niraparib has peculiar pharmacokinetics proprieties such as higher volume of distribution Vd and blood-brain barrier BBB penetration These characteristics lead to a progressive drug accumulation in brain and other body tissues with standard daily administration reaching concentration well over that necessary for PARP inhibition Overall Niraparib can represent an ideal candidate to explore for treatment of malignant gliomas and a non-continuous administration may lead to a reduced bone marrow exposure decreasing haematological toxicity without compromising anticancer activity
Previous clinical experiences have already explored PARP inhibitors combined to TMZ in solid malignancies with scarce tolerability mainly due to bone marrow exhaustion In one small trial a continuous administration of Niraparib in combination with standard schedule TMZ across several cohorts confirmed high rate of hematologic toxicities and interestingly showed signals of activity in glioblastoma GBM
Considering the peculiar pharmacokinetics proprieties of Niraparib and the recovery in MGMT activity described for dd-TMZ investigator speculate that different schedules and doses of the two drugs compared to the ones approved in clinical practice may be explored to improve tolerability preserving the synergistic activity
TMZ is a DNA-methylating chemotherapeutic agent with good CNS penetration Its mechanism of action is increased by either gene promoter methylation or consumption of the methylguanine-DNA methyltransferase MGMT an enzyme repairing chemotherapy-induced genome damages
Alternative intensified schedules of TMZ dose-dense TMZ dd-TMZ can give patients an increased total dose of drugs per each cycle progressively consuming MGMT and overcoming resistance of cancer cells to standard first-line schedule They are usually used at disease recurrence with a tolerable safety profile For example a clinical study testing the 7 day on 7 day off schedule showed that MGMT activity in blood mononuclear cells decreased at day 8 and progressively recovered during the week-off This may limit haematological toxicity
The inhibition of Poly ADP-ribose polymerase PARP proteins normally involved in genomic stability may rationally improve TMZ efficacy Switching off PARP molecules can block both base-excision repair BER system and Poly-ADP ribose-ylation of MGMT a key process for its function leading to an amplification in DNA damages In the subset of Isocitrate dehydrogenase IDH 12 mutant gliomas the enzyme leads to 2-hydroxy-glutarate 2HG accumulation in cancer cells This onco-metabolite increases sensitivity to DNA damages by alkylating agents and induces a Breast Cncer geneBRCA-ness phenotype indeed Considering all this the use of PARP inhibitors seems promising even for these patients
When compared to other PARP inhibitors Niraparib has peculiar pharmacokinetics proprieties such as higher volume of distribution Vd and blood-brain barrier BBB penetration These characteristics lead to a progressive drug accumulation in brain and other body tissues with standard daily administration reaching concentration well over that necessary for PARP inhibition Overall Niraparib can represent an ideal candidate to explore for treatment of malignant gliomas and a non-continuous administration may lead to a reduced bone marrow exposure decreasing haematological toxicity without compromising anticancer activity
Previous clinical experiences have already explored PARP inhibitors combined to TMZ in solid malignancies with scarce tolerability mainly due to bone marrow exhaustion In one small trial a continuous administration of Niraparib in combination with standard schedule TMZ across several cohorts confirmed high rate of hematologic toxicities and interestingly showed signals of activity in glioblastoma GBM
Considering the peculiar pharmacokinetics proprieties of Niraparib and the recovery in MGMT activity described for dd-TMZ investigator speculate that different schedules and doses of the two drugs compared to the ones approved in clinical practice may be explored to improve tolerability preserving the synergistic activity
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