Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC).

TPS2072 Background: The standard treatment for patients with newly diagnosed glioblastoma comprises maximum safe surgery, radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Despite this intense therapy, the prognosis remains poor and there is an urgent need to develop new therapeutic options. Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor. Following its successful assessment in phase I trials in patients with newly diagnosed as well as recurrent glioblastoma, marizomib is now being investigated in a phase III trial. Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase III superiority trial. Eligibility criteria include histologically confirmed newly diagnosed glioblastoma and a performance status ≥70. Approximately a total of 750 patients will be enrolled and randomized 1:1. Stratification factors include institution, age, Karnofsky performance status and extent of surgery. The primary objective of this study is to compare overall survival in patients receiving marizomib in addition to standard of care (TMZ/RT→TMZ) with patients receiving standard treatment only. The testing strategy specifies the determination of this objective in both the intent-to-treat population and the subgroup of patients with tumors harboring an unmethylated MGMT promoter. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. The study is accompanied by a translational research program. The study will be opened at 50 EORTC sites in Europe and done as an intergroup collaboration with the Canadian Cancer Trials Group (CCTG) with 25 sites in Canada and additional sites in the US. Patient enrolment started in June 2018 and as of January 29, 2019, a total of 85 patients have been randomized. An update on the enrolment status will be provided at the ASCO conference. Clinical trial information: NCT03345095.

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Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.6650 ◽

2010 ◽

Vol 28 (16) ◽

pp. 2712-2718 ◽

Cited By ~ 286

Author(s):

Roger Stupp ◽

Monika E. Hegi ◽

Bart Neyns ◽

Roland Goldbrunner ◽

Uwe Schlegel ◽

...

Keyword(s):

Phase I ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Mgmt Promoter Methylation ◽

Newly Diagnosed ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma

Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.

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EPIG-18PYROSEQUENCING ANALYSIS OF THE MGMT PROMOTER METHYLATION STATUS IN NEWLY DIAGNOSED GLIOBLASTOMA CORRELATES WITH VOLUMETRIC CHANGES OF UNRESECTED ENHANCED LESIONS IN MRI AFTER STANDARD RADIATION AND TEMOZOLOMIDE THERAPY

Neuro-Oncology ◽

10.1093/neuonc/nov214.18 ◽

2015 ◽

Vol 17 (suppl 5) ◽

pp. v90.2-v90

Author(s):

Masamichi Takahashi ◽

Yuko Matsushita ◽

Yasuji Miyakita ◽

Makoto Ohno ◽

Takahiro Ogawa ◽

...

Keyword(s):

Promoter Methylation ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Newly Diagnosed ◽

Promoter Methylation Status ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma ◽

Mgmt Promoter Methylation Status

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MGMT Promoter Methylation Status Can Predict the Incidence and Outcome of Pseudoprogression After Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma Patients

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(09)79139-2 ◽

2009 ◽

Vol 2009 ◽

pp. 122-123

Author(s):

J. Uhm

Keyword(s):

Promoter Methylation ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Newly Diagnosed ◽

Concomitant Radiochemotherapy ◽

Promoter Methylation Status ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma ◽

Mgmt Promoter Methylation Status

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MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2051 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2051-2051

Author(s):

K. D. Aldape ◽

G. Jones ◽

M. Wang ◽

M. Hegi ◽

R. C. Janzer ◽

...

Keyword(s):

Clinical Trial ◽

Real Time ◽

Promoter Methylation ◽

Mgmt Promoter Methylation ◽

Phase Iii ◽

Major Advance ◽

Newly Diagnosed ◽

Mgmt Methylation ◽

Mgmt Promoter ◽

Central Pathology

2051 Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens. No significant financial relationships to disclose.

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