This human Phase 1 trial is a continuation of a Phase 1 trial which enrolled patients with
recurrent gliomas (#TJU-14379-101) and which was designed after a previously conducted Phase
1 human trial at our institution. With certain modifications, it is intended to reproduce the
safety results of the recurrent glioma previous trials as well as explore any objective
clinical responses in newly diagnosed patients. Protocol 14379-101 is closed to accrual and
Abbreviated Clinical Report is prepared for FDA submission. The safety profile for this
protocol was quite favorable.
This treatment involves taking the patient's own tumor cells at surgery, treating them with
an investigational new drug (an antisense molecule) designed to shut down a targeted surface
receptor protein, and re-implanting the cells, now encapsulated in small diffusion chambers
the size of a nickel in the patient's abdomen within 24 hours after the surgery. Loss of the
surface receptor causes the tumor cells to die in a process called apoptosis. As the tumor
cells die, they release small particles called exosomes, each full of tumor antigens. The
investigators believe that these exosomes as well as the presence of the antisense molecule
work together to activate the immune system against the tumor as they slowly diffuse out of
the chamber. Immune cells are immediately available for activation outside of the chamber
because a wound was created to implant these tumor cells and a foreign body (the chamber) is
present in the wound. In this trial, a dose escalation of the therapeutic agent will involve
an increase in both biodiffusion chamber number as well as the time the biodiffusion chambers
remain implanted. The wound and the chamber fortify the initial immune response which
eventually leads to the activation of immune system T cells that attack and eliminate the
tumor. By training the immune system to recognize the tumor, the patient is also protected
through immune surveillance from later tumor growth should the tumor recur. Compared to
treatment alternatives for tumor recurrence, including a boost of further radiation and more
chemotherapy, this treatment represents potentially greater benefit with fewer risks.
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.
- Documentation by MR of a gadolinium-enhancing intraparenchymal mass consistent with
- 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.
- 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
- 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