Antisense102: Pilot Immunotherapy for Newly Diagnosed Malignant Glioma

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.

Sex

All

Minimum age

18 Years

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

• BACKGROUNDAndrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken RD. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol. 2001 Apr 15;19(8):2189-200. doi: 10.1200/JCO.2001.19.8.2189. PMID 11304771
• DERIVEDAndrews DW, Judy KD, Scott CB, Garcia S, Harshyne LA, Kenyon L, Talekar K, Flanders A, Atsina KB, Kim L, Martinez N, Shi W, Werner-Wasik M, Liu H, Prosniak M, Curtis M, Kean R, Ye DY, Bongiorno E, Sauma S, Exley MA, Pigott K, Hooper DC. Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res. 2021 Apr 1;27(7):1912-1922. doi: 10.1158/1078-0432.CCR-20-3805. Epub 2021 Jan 26. PMID 33500356