NCT06258018

Niraparib and Temozolomide in Patients Glioblastoma

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
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 86 (estimated)
• Sponsor: Armando Santoro, MD · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

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) 1/2 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 gene(BRCA)-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.

Conditions

• Glioma, Malignant

Interventions

Type	Name	Description
DRUG	Temodal	given orally for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days
DRUG	Niraparib	given orally in continous

Timeline

• Start date: 2024-09-01
• Primary completion: 2026-12-01
• Completion: 2027-09-01
• First posted: 2024-02-14
• Last updated: 2024-08-30

Locations

1 site across 1 country: Italy