Glioma is a type of tumor that occurs in the brain and spinal cord. According to the NIH/NCI, brain and other nervous system tumors account for 1.4% of all new cancer cases and 2.9% of all cancer-related deaths. In 2019, an estimated 23,820 new cases of will be diagnosed and 17,760 patients will die from these tumors.
Approximately 50% of all primary brain tumors originate from astrocytes, one of the subtypes of the nonneuronal supportive glial cells of the brain. Primary brain tumors that develop from astrocytes are called astrocytomas. The World Health Organization (WHO) classifies astrocytomas into four distinct grades (I,II,III,IV) on the basis of how quickly the cells grow and spread and how the cells appear under a microscope. Collectively, the Grade III and IV gliomas are referred to as high grade gliomas. Glioblastoma (Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults.
Glioblastoma (GBM) – A High Grade (Most Serious) Glioma
According to the most recent CBTRUS Statistical Report, annually there are approximately 12,900 cases of glioblastoma diagnosed, with historical 1 year and 5 year relative survival rates of 40.8% and 6.8%, respectively. The poor survival is attributable partly to the nature of the tumor. The infiltrative nature of glioblastoma results in difficulty eliminating microscopic disease despite macroscopic gross-total resection, with 90% of patients having recurrence at the original tumor location. The location of the tumor also makes drug delivery difficult with only small or lipophilic molecules able to cross the blood brain barrier to reach the tumor. Of those agents that are able to reach the tumor, glioblastomas have shown to be resistant to most cytotoxic agents and to quickly develop resistance when initially sensitive. The most significant advance in treatment for glioblastoma over the last several years has come from concomitant chemoradiotherapy with temozolomide which can result in increased median survival of 14.6 months with radiotherapy plus temozolomide compared to 12.1 months with radiotherapy alone. However, this still leaves much to be desired with an improvement in median survival of only 2.6 months over radiotherapy alone. In the recurrent and progressive setting there is no clear standard of care. More recent studies have shown that some benefit can be seen at the time of progression with angiogenesis inhibitor bevacizumab, achieving median progression free survivals of 22- 23 weeks, and median overall survivals of 40 to 54 weeks. Nevertheless, despite recent advances, glioblastoma remains incurable with a life expectancy of less than 24 months despite all efforts.
Note: all external links
- American Brain Tumor Association
- American Cancer Society
- Brain Tumor Network
- Dictionary of Cancer Terms
- End Brain Cancer Initiative
- MedlinePlus (NIH)
- National Brain Tumor Society
- National Cancer Institute
- National Comprehensive Cancer Network
- Support Groups Listing
- The Brain Tumour Charity
- Trial Connect
- Voices Against Brain Cancer
Standard Treatment for Glioblastoma
Glioblastoma (Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults, and hence the primary target of drug development for intracranial malignancy. Currently, front-line treatment consists of a multi-modality approach that includes maximal surgical resection, adjuvant radiation therapy of 54-60 Gy with concurrent temozolomide at 75 mg/m2, 6 months of single-agent temozolomide at up to 200 mg/m2 with tumor treatment fields (TTF). This multimodal approach results in a median overall survival of 19.6 months in the intent to treat population. While this is an improvement, it is clear that radiation remains the most effective component of the combined approach with multiple randomized studies showing a 5 month improvement in survival with XRT alone compared to an additional 2.5 months with the addition of chemotherapy and 3 months for TTF.
Once a patient fails standard front-line therapy, prognosis is very poor. The only currently approved therapeutic for salvage treatment is bevacizumab, a recombinant humanized monoclonal antibody against VEGF with an associated median overall survival time of 8.7-9.2 months. After bevacizumab failure, survival is only approximately 120 days.
Rhenium-186 NanoLiposome (186RNL) have shown great promise in preclinical studies of glioblastoma that surpassed results typically seen with current standard treatment modalities such as oral temozolomide or intravenous bevacizumab. Glioblastoma remains incurable with limited benefit despite aggressive treatment. Investigation of RNL safety and tolerability is warranted.
186RNL’s lipid nanocarrier is an essential component for radionuclide retention. The ability to treat the whole tumor is also greatly enhanced by the 2 millimeter average path length of the beta particle radiation which compensates for mild inhomogeneities in the CED dispersion of the nanoparticles within the tumor. The 2 millimeter pathlength means that therapy delivered to one cell has the potential of moving through 80 cell diameters since an average cell diameter is 25 microns (25 x 80 cell diameters = 2 millimeter pathlength). Another theoretical advantage for the local administration of rhenium-labeled nanoliposomes is that the glial originating cells of the tumor retain their phagocytic ability and may be actively ingesting the nanoparticles which would result in a specific targeting of glioblastoma cells as compared with normal glial and neuronal cells.
Rhenium-186 NanoLiposome (RNL) intracranially administered by convection-enhanced delivery (CED) using cannulas specifically designed for use in the brain.
ReSPECT™-GBM CLINICAL TRIAL: RECRUITING PATIENTS
In the U.S. multi-center ReSPECT™ Phase 1/2 clinical trial supported by the National Institutes of Health / National Cancer Institute, 186RNL (Rhenium-186 NanoLiposome) is being evaluated in patients with recurrent glioblastoma GBM.
Interim data from the ongoing clinical trial shows that the administration of 186RNL, which is designed to allow for targeted beta radiation to the tumor via convection enhanced delivery (CED) with limited exposure to surrounding tissues, was well tolerated in adult patients with recurrent GBM at significantly higher doses than with standard treatment modalities such as external beam radiation therapy (EBRT).
PLUS THERAPEUTICS is conducting the ReSPECT™ clinical study under a U.S. FDA approved Investigational New Drug (IND) application.
In September 2020, PLUS THERAPEUTICS announced that the U.S. FDA granted both an Orphan Drug designation and a Fast Track designation for its lead investigational drug, Rhenium-186 NanoLiposome (186RNL) for the treatment of patients with recurrent glioblastoma.
The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the U.S. Orphan drug designation provides to the Company certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.
The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions.