Carboplatin combined with the vascular-disrupting agent CYT997 for recurrent glioblastoma multiforme.

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e13591 Background: The outcome in recurrent glioblastoma multiforme (GBM) remains poor although recent experience with regimens that include an anti-angiogenesis agent have shown some promise. We initiated a phase Ib trial of an alternative approach to vascular targeting, which evaluates the combination of the vascular-disrupting agent CYT997 with carboplatin. Methods: Patients with recurrent GBM after frontline radiation and temozolomide initially received carboplatin AUC=5 day 1 and etoposide 100 mg/m2 days 1-3, combined with CYT997 by 24-hour continuous IV infusion beginning day 2. Treatment was repeated every 3 weeks. Etoposide was deleted from the regimen after the first 4 patients due to excessive myelotoxicity. MRI scans were repeated every 2 cycles for response assessment and DCE-MRI scans were used to evaluate vascular disruption after the first cycle. Results: Eight patients have received at least one cycle of study therapy. The starting dose of CYT997 was 150 mg/m2. On day 5 of cycle 1, the first patient developed expressive dysphasia due to a left hemisphere infarct (confirmed on MRI with diffusion-weighted images). Subsequent CT angiography revealed a tight stenosis of the left MCA in the region of the previous high-dose radiation field. A protocol amendment then de-escalated the CYT997 dose and mandated screening magnetic resonance angiography and exclusion of patients with hemodynamically-significant cerebrovascular stenoses. Six patients have subsequently received CYT997 at 100 mg/m2 and one patient at 125 mg/m2 without further cerebrovascular toxicities. DCE-MRI showed reduced tumor Ktrans consistent with vascular disruption in 3 out of 6 evaluable patients. One patient had an imaging partial response after 3 cycles, but stopped protocol treatment because of worsening of pre-existing hydrocephalus and neurological deterioration. Another patient remains on study with stable disease after 8 cycles. Conclusions: Treatment with carboplatin and the vascular-disrupting agent CYT997 is feasible in recurrent GBM. Ongoing patient accrual will determine the efficacy of this regimen and the potential role of screening magnetic resonance angiography in avoiding cerebrovascular toxicity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cytopia Research Pty, Ltd Cytopia Research Pty, Ltd Cytopia Research Pty, Ltd