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.

Ultrasound Molecular Imaging of the Breast Cancer Neovasculature using Engineered Fibronectin Scaffold Ligands: A Novel Class of Targeted Contrast Ultrasound Agent

“…FN3 VEGFR2 is a scaffold with high affinity to human VEGFR2 with simultaneous introduction of cross-reactivity to murine VEGFR2 25. It has shown good safety profile in phase I and II clinical trials in patients used as an anti-angiogenic drug 26, 27. The absence of cysteine and lysine residues near the engineered binding loops of FN3-scaffolds allows site-specific coupling of the ligand to the MB shell without compromising binding affinity.…”

“…In contrast to antibodies, they are inexpensive to produce in large quantities, because of their relatively small size, solubility, and the lack of glycosylation and disulfide bonds 18-24. A VEGFR2-targeted FN3-scaffold (FN3 VEGFR2 ) for therapeutic purposes has been shown to be safe in patients in early clinical trials 25-27.…”

Mechanisms of action of therapeutic antibodies for cancer

“…CT322 is an adnectin that binds to and inhibits VEGFR2 [241]. A recent phase II clinical trial failed to demonstrate efficacy in glioblastoma patients and was terminated early[242]. A phase II study of CT322 for NSCLC failed to show that this adnectin improved outcomes in comparison to paclitaxel/carboplatin plus Bevacizumab[243].…”

Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy

“…Although there are promising results and clinical improvements, the overall survival has not been prolonged in the new randomized phase II-III trials of bevacizumab in diagnosed GBM [69][70][71]. Despite aggressive therapy with maximal safe surgical resection, radiation and chemotherapy, GMBs invariably are refractory to or become resistant to treatment and recur [72].…”