Phase 2 study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma.

Abstract

VEGF signaling through VEGFR-2 is the major factor in glioblastoma angiogenesis. CT-322, a pegylated protein engineered from the 10th type III human fibronectin domain, binds the VEGFR-2 extracellular domain with high specificity and affinity to block VEGF-induced VEGFR-2 signaling. This study evaluated CT-322 in an open-label run-in/phase 2 setting to assess its efficacy and safety in recurrent glioblastoma. Eligible patients had 1st, 2nd or 3rd recurrence of glioblastoma with measurable tumor on MRI and no prior anti-angiogenic therapy. The initial CT-322 dose was 1 mg/kg IV weekly, with plans to escalate subsequent patients to 2 mg/kg weekly if tolerated; within each CT-322 dose cohort, patients were randomized to ±irinotecan IV semiweekly. The primary endpoint was 6-month progression-free survival (PFS-6). Sixty-three patients with a median age of 56 were treated, the majority at first recurrence. One-third experienced serious adverse events, of which four were at least possibly related to study treatment (two intracranial hemorrhages and two infusion reactions). Twenty-nine percent of subjects developed treatment-emergent hypertension. The PFS-6 rate in the CT-322 monotherapy groups was 18.6 and 0.0 % in the 1 and 2 mg/kg treatment groups, respectively; results from the 2 mg/kg group indicated that the null hypothesis that PFS-6 ≤12 % could not be rejected. The study was terminated prior to reaching the planned enrollment for all treatment groups because data from the completed CT-322 2 mg/kg monotherapy treatment arm revealed insufficient efficacy. Despite biological activity and a tolerable side effect profile, CT-322 failed to meet the prespecified threshold for efficacy in recurrent glioblastoma.

• Authors: David Schiff, Santosh Kesari, John de Groot, Tom Mikkelsen, Jan Drappatz, Thomas Coyle, Lisa Fichtel, Bruce Silver, Ian Walters, David Reardon
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 1 Pg. 247-53 (Feb 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25388940 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• CT-322
• Fibronectins
• Peptide Fragments
• Protein Kinase Inhibitors
• UGT1A1 enzyme
• Glucuronosyltransferase
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, therapeutic use)
• Brain Neoplasms (drug therapy, genetics)
• Disease-Free Survival
• Female
• Fibronectins (adverse effects, therapeutic use)
• Glioblastoma (drug therapy, genetics)
• Glucuronosyltransferase (genetics)
• Humans
• Male
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Peptide Fragments (adverse effects, therapeutic use)
• Polymorphism, Genetic
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)