Antisense102: Pilot Immunotherapy for Newly Diagnosed Malignant Glioma

This trial will be an adaptation of Protocol 101 which recently closed after rapid and complete accrual, now with an escalation of the induction vaccination in four cohorts. For practical purposes, a standard dose-escalation study is not possible with the current paradigm. Although the investigators may have identified a distinct bioactive byproduct of Insulin-like growth factor receptor-1 Antisense Oligodeoxynucleotide (IGF-1R/AS ODN)-induced tumor cell apoptosis (exosomes), it is difficult to perform a dose escalation in a typical fashion. Also, antigen concentration can affect immune response in a biphasic manner: too little or too much can dampen an immune response, so even if the antigen or antigens were known, a typical pharmacologic dose escalation would not follow typical pharmacokinetics. For these reasons, in Protocol 102, 32 patients will have therapy at initial surgery followed by implantation of 20 chambers for a duration of 48 hours. There was a documented increase in tumor infiltrating lymphocytes after treatment in our original trial, this observation provided preliminary supporting evidence that this therapeutic vaccine will elicit an adaptive immune response. Protocol 102 has been designed to further elucidate an immune response with a quantitative assessment of tumor specific T cells as well as circulating M2 macrophages before and after treatment. The design of the Phase 1 trial will allow a statistical analysis of both antigen dose (number of chambers) and time of exposure (chamber dwell time) as either variable may relate to any toxicity or treatment response.

A summary of the treatment paradigm includes: Pre-operative plasma leukopheresis, then surgery with tissue harvest and implantation of 20 diffusion chambers in the rectus sheath with IGF-1R/AS ODN as previously reported within 24 hours of craniotomy, implanted for 48 hours. All patients who meet the eligibility criteria and agree to participate in this study will be potential candidates for therapy.

Inclusion criteria

• Documentation by MR of a gadolinium-enhancing intraparenchymal mass consistent with malignant glioma.
• Frozen section diagnosis of WHO Grade IV glioma, confirmed with permanent section and immunopositive for IGF-1R.
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or a Karnofsky Performance Score (KPS) of at least 60.
• Must be 18 years of age or older.
• Must sign an approved informed consent.
• Hemodynamically stable, consistent with Standard of Care values for patients undergoing elective tumor resection.

Exclusion criteria

• Females who are pregnant, nursing, or not inclined to use adequate contraceptive methods if necessary to prevent pregnancy during the study.
• An active second primary malignancy with the exception of basal cell or squamous cell skin carcinoma.
• Major concomitant medical illness inclusive of severe chronic obstructive pulmonary disease, multiple sclerosis, symptomatic coronary artery disease, heart failure, recent major cerebrovascular accident, brittle diabetes, renal dialysis, end stage liver disease, labile hypertension, or any autoimmune disorder.
• A history of heparin-induced thrombocytopenia or hypersensitivity to heparin, enoxaparin, or pork products.
• An abnormal International Normalized Ratio (INR) of greater than 1.3, if repeatable and refractory to correction by routine methods.
• Documented deep venous thrombosis