Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma

Abstract

Oligodeoxynucleotides containing CpG motifs (CpG ODNs) display a strong immunostimulating activity and drive the immune response toward the Th1 (T helper type 1) phenotype. These ODNs have shown promising efficacy in preclinical studies when injected locally in several cancer models. We conducted a phase 1 trial to define the safety profile of CpG-28, a phosphorothioate CpG ODN, administered intratumorally by convection-enhanced delivery in patients with recurrent glioblastoma. Cohorts of three to six patients were treated with escalating doses of CpG-28 (0.5-20 mg), and patients were observed for at least four months. Twenty-four patients entered the trial. All patients had previously been treated with radiotherapy, and most patients had received one or several types of chemotherapy. Median age was 58 years (range, 25-73) and median KPS was 80% (range, 60%-100%). Adverse effects possibly or probably related to the studied drug were moderate and consisted mainly in worsening of neurological conditions (four patients), fever above 38 degrees C that disappeared within a few days (five patients), and reversible grade 3 lymphopenia (seven patients). Only one patient experienced a dose-limiting toxicity. Preliminary evidence of activity was suggested by a minor response observed in two patients and an overall median survival of 7.2 months. In conclusion, CpG-28 was well tolerated at doses up to 20 mg per injection in patients with recurrent glioblastoma. Main side effects were limited to transient worsening of neurological condition and fever.

Fig. 1

Brain MRI studies of patient 9. Before administration of CpG oligodeoxynucleotide (ODN), gadolinium-enhanced sections (a–c) and fluid-attenuated inversion recovery (FLAIR) sequence (d) showed a recurrent tumor in the right temporal lobe with surrounding edema. Thirty days after administration of CpG ODN, the area of contrast enhancement, the surrounding edema, and the mass effect were reduced at the site of injection (e–h).

Fig. 2

Brain MRI studies of patient 17. At time of inclusion, gadolinium-enhanced sections (a–c) showed recurrence in the right temporal lobe. MRI performed 30 days (d–f) and 60 (g–i) days after administration showed a minor response at the site of injections. Reduction of surrounding edema was also noted (not shown). A small recurrence occurred on the external part of the temporal lobe (g).

Fig. 3

Kaplan–Meier estimate of overall survival.