Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

Abstract

3065^ Background: TLR9 agonists, such as phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs), are immunostimulating agents with antitumor effects in animal models. Neoplastic meningitis is a devastating disease, with no efficient therapeutic available. A phase I trial was conducted in patients with neoplastic meningitis to define the safety profile of subcutaneous injections, combined or not with intra-CSF administration of a CpG ODN. Methods: The diagnostic of neoplastic meningitis was based on a positive CSF cytology or on the association of clinical symptoms with meningeal enhancement on MRI. Cohorts of 3-6 patients were treated for 5 weeks with escalating doses of CpG-28 (level 1 and 2: 0.1and 0.3 mg/kg/week subcutaneously (sc); level 3 to 6: 0.3mg/kg sc associated with 3/7/12/18 mg intrathecally every other week). Concomittant treaments with radiotherapy or chemotherapy were allowed. The primary endpoint was tolerance. Secondary endpoints were time until neurological progression and survival. Results: Twenty-nine (29) patients were included. Primary cancer was malignant glioma (n=15), lung carcinoma (n=7), breast cancer (n=3), melanoma or melanocytoma (n=2), ependymoma (n=1), and colorectal cancer (n=1). At diagnosis median age was 56 years and median KPS was 70%. The treatment was well tolerated. Adverse effects possibly or probably related to the studied drug consisted in grade 2 lymphopenia, anemia and neutropenia (n=19), local erythema at injection sites (n=14), fever (n=10) and seizure (n=11). Two serious adverse events were considered as possibly or probably related to the protocol: one local infection and one intra-cerebral haemorrhage. Interestingly, median survival was higher in patients (n=8) who were concomitantly treated with bevacizumab a time of protocol (19 weeks vs 15 weeks, p=0.11). Conclusions: CpG-28 was well tolerated at doses up to 0.3mg/kg subcutaneously and 18 mg intrathecally. Main side effects were limited to local erythema, lymphopenia and fever. Combination with bevacizumab warrants further clinical investigations. Clinical trial information: P060301.