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Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial

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Abstract

Newly diagnosed glioblastoma multiforme with unmethylated MGMT promoter has a poor prognosis, with a median survival of 12 months. This phase II study investigated the efficacy and safety of combining the selective integrin inhibitor cilengitide with a combination of metronomic temozolomide and procarbazine for these patients. Eligible patients (newly diagnosed, histologically confirmed supratentorial glioblastoma with unmethylated MGMT promoter) were entered into this multicentre study. Cilengitide (2000 mg IV twice weekly) was commenced 1 week prior to radiotherapy combined with daily temozolomide (60 mg/m2) and procarbazine (50 or 100 mg) and, after 4 weeks’ break, followed by six adjuvant cycles of temozolomide (50–60 mg/m2) and procarbazine (50 or 100 mg) on days 1–20, every 28 days. Cilengitide was continued for up to 12 months or until disease progression or unacceptable toxicity. The primary endpoint for efficacy was a 12-month overall survival rate of 65 %. Twenty-nine patients completed study treatment. Sixteen patients survived for 12 months or more, an overall survival rate of 55 %. The median overall survival was 14.5 months (95 % CI 11.1–19.6) and the median progression-free survival was 7.4 months (95 % CI 6.1–8). Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation.

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Acknowledgments

This study was funded by an independent research grant from Merck Serono (Merck KGaA), Darmstadt, Germany.

Author information

Authors and Affiliations

  1. Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia

    Mustafa Khasraw, Adrian Lee, Sally McCowatt, Zoltan Kerestes, Michael Back & Helen Wheeler

  2. University of Sydney, Sydney, Australia

    Mustafa Khasraw, Adrian Lee, Michael Back & Helen Wheeler

  3. NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia

    Mustafa Khasraw

  4. International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium

    Marc E. Buyse & Ganessan Kichenadasse

  5. Flinders Medical Centre and Flinders University, Adelaide, Australia

    Ganessan Kichenadasse

  6. Calvary Mater Newcastle Hospital, Newcastle, Australia

    Stephen Ackland

  7. Royal North Shore Hospital, Pacific HWY, St Leonards, NSW, 2065, Australia

    Mustafa Khasraw

Authors
  1. Mustafa Khasraw
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  2. Adrian Lee
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Corresponding author

Correspondence to Mustafa Khasraw.

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Conflicts of interest

The institutions of MK, SM, ZK, AL, M Back and HW (RNSH) received research funding from Merck Serono/Merck KGaA for the conduct of this study. Marc Buyse is an employee of IDDI (International Drug Development Institute) and holds stock in IDDI. MK and HW have served on Roche GBM advisory board. MK has served on Abbvie GBM advisory board. All other authors declare no conflict of interest.

Appendix 1: Modified Macdonald criteria for radiologic assessment

Appendix 1: Modified Macdonald criteria for radiologic assessment

The primary criterion for assessment of efficacy was median overall survival. Further clinical activity, measured as progression-free survival and response, was assessed by gadolinium-enhanced magnetic resonance imaging, neurologic examination, and steroid use, as outlined in the table:

Clinical status

Clinical activity assessments

Neuroimaging Gd-MRI

Neurologic examination

Steroid use

Complete response

Disappearance of all enhancing tumor, and

No new lesions

Stable or improved compared to the most recent neurologic examination

None

Partial response

≥50 % reduction in the sum of the products of the largest perpendicular diameters of enhancing tumour compared to the baseline sum,

No worsening of an evaluable lesion(s), and

No new lesions

Stable or improved compared to the most recent neurologic examination

Same or lower dose compared to the dose at previous scan, and

Dose is stable for ≥72 h prior to each scan

Progressive disease

≥25 % increase in the sum of the product of the largest perpendicular diameters of enhancing tumour compared to the smallest prior sum,

Worsening of an evaluable lesion(s), or

Any new lesion(s)

Worsening compared to the most recent neurological examination [3]

Increasing dose of steroids may be taken into account for judgment

Stable disease

Neither response (complete or partial) nor progressive disease

  1. To qualify as a complete or partial response, all three criteria of neuroimaging, neurological examination, and steroid use, were required

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Khasraw, M., Lee, A., McCowatt, S. et al. Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial. J Neurooncol 128, 163–171 (2016). https://doi.org/10.1007/s11060-016-2094-0

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  • DOI: https://doi.org/10.1007/s11060-016-2094-0

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