Dataset Information

A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

ABSTRACT:

Background

Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.

Methods

VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.

Results

A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.

Conclusion

The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

SUBMITTER: Sim HW

PROVIDER: S-EPMC8485443 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND Glioblastoma (GBM) is the most malignant primary brain tumor in adults where median survival in unselected patients is approximately 10 months. There is no standard treatment for patients who progress on temozolomide and patients are best treated within investigational clinical protocols. Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme have particularly poor prognosis with median overall survival of 12.7 months, compared to 21.7 months for patients with hypermethylated MGMT promoter. The pre-clinical studies have shown that Bortezomib depletes the MGMT enzyme, restoring the tumour ´s susceptibility to Temozolomide, if the chemotherapy is administered in the precise schedule when the MGMT enzyme is depleted. Additionally, Bortezomib shows an antitumour effect by blocking autophagy flux. Based on the promising pre-clinical results, a non-randomized, open label phase IB/II clinical trial was designed. The primary endpoints include assessment of safety of Bortezomib administered with Temozolomide for phase IB and median progression free survival, overall survival as well as progression free rate at 6 months. MATERIAL AND METHODS Recurrent glioblastoma patients with unmethylated MGMT promotor, progressing at least 12 weeks after completion of postoperative radiotherapy, with adequate organ function, performance status Karnofsky 70 or better and radiologically measurable lesions are screened for study inclusion. The experimental treatment consists of Bortezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with per oral Temozolomide at 200mg/m2 5 days/week every 4 weeks starting on day 3. Study group will be compared to historical controls on conventional management. The sample size was calculated to 63 patients, ten of them were included in the phase IB. RESULTS The phase IB of the trial was completed in 2019 and the combination of Temozolomide and Bortezomib was shown to be safe and well tolerated. Until April 2021 a total number of 23 patients were included into the trial. The patients are treated at 4 different referral university hospitals in Norway. A clinical treatment benefit with both radiological tumor volume response and stable disease were observed. The patient inclusion in the trial is delayed due COVID-19. The majority of observed side effects are mild or moderate. The grade 3 or 4 adverse effects included thrombocytopenia, ataxia, muscle weakness, delirium and hyperglycemia. Patients that progressed under the treatment received another line of therapy according to the institutional practice. CONCLUSION A combination of Bortezomib and Temozolomide administered in a defined time sequence to achieve sensitization of glioblastoma to alkylating agent is safe and feasible and may represent a novel treatment option for patients with this devastating disease.

Project description:BackgroundSensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed.MethodsThe efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction.ResultsThe combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines.ConclusionVeliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.