Home News Novel Australian Drug GDC-0084 Included in Phase II Adaptive Trial for GBM
Novel Australian Drug GDC-0084 Included in Phase II Adaptive Trial for GBM
Peter Hofland, Ph.D
A phase II clinical trial of GDC-0084 (Kazia Therapeutics), a drug that targets the signaling pathway implicated in about 90% of cases of the deadly brain cancer glioblastoma multiforme (GBM) has opened at the Stephenson Cancer Center at the University of Oklahoma. The trial targets newly-diagnosed patients resistant to currently used standard treatment. Using an adaptive study design, the researchers involved in the trial, expect to see initial data read out on optimal dose in early 2019. This is followed by definitive evidence of clinical efficacy.
The standard treatment for GBM includes radiation plus the chemotherapeutic agent temozolomide (TMZ).? The cytotoxic effects of TMZ is primarily due to alkylation of DNA, leading to DNA damage and tumor cell death. As a monofunctional methylating agent, TMZ is a member of one of the oldest class of anticancer drugs still commonly used. These agents generally work by reacting with proteins that bond together to form the double helix DNA structure. By adding an alkyl group to some or all of these proteins they are prevented from linking which causes breakage of the DNA strands. This, in turn,leads to the death of the cancer cell.? This mechanism of action, which can be considered a mutation, that takes away the cancer?s ability to multiply. However, activation of the PI3K/Akt/mTOR pathway, which leads to the development of drug resistance,? dampens the therapeutic effects of TMZ.
GDC-0084 is a potential alternative treatment option for the two thirds of patients resistant to the mainstay of current pharmacological treatment for GBM, temozolomide. [1]
GBM is the most common and aggressive form of primary brain cancer, exhibiting a high rate of recurrence and poor prognosis due to the invasive nature of the tumor. About 12,500 patients in the US [2] and 1600 patients in Australia [3] are diagnosed with glioblastoma each year. Left untreated, patients will only live on average for 3-4 months [4], and even with the best available care, the median survival rate for patients is around 12-15 months [5]. In adults, the five year survival rate for glioblastoma is less than 5%.
GDC-0084 is being developed as an inhibitor of the PI3K signaling pathway, which is implicated in most cases of glioblastoma.
The investigational drug is distinguished from other brain cancer drugs being developed by its ability to cross the blood-brain barrier which lines the brain microvasculature and allows for passage of O2, CO2, and glucose as required for brain cell metabolism. However, because of high resistance tight junctions between microvascular endothelial cells transport of most polar solutes, and, as a result, many drugs are unable to fully affect the brain.
Last month, GDC-0084 was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA), recognising the drug as a potential treatment for a rare disease with high unmet patient need.
Kazia Therapeutics in-licenced GDC-0084 from Genentech after a successful Phase I safety study also showed signs of efficacy.
?The need for new therapies for glioblastoma remains immense – clinical trials of a variety of potential new therapies are ongoing, but we haven?t yet seen a very convincing new treatment option emerge,? noted James Garner Chief Executive Officer and Executive Director of Kazia Therapeutics, an innovative oncology-focused biotechnology company, based in Sydney, Australia.
?One reason is that many of the drugs being tried are really intended for use in other tumor types, and are only tested in glioblastoma via small and speculative clinical trials. In contrast, GDC-0084 was designed specifically as a treatment for brain cancer, so it has been very carefully optimized for this disease area. The work on the drug to date has been of an exceptionally high standard, Garner explained.
?We are excited to now have the trial underway, and look forward to working with the participating clinicians,? he added.
Last Editorial Review: March 28, 2018
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brain cell metabolism
PI3K/Akt/mTOR pathway
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Peter Hofland, Ph.D is the Executive Editor of ADC Review/Journal of Antibody-drug Conjugates, a comprehensive digital platform and peer reviewed publication focusing on news and information about innovative therapies such as Antibody-drug Conjugates (ADCs). Hofland contributes articles on the advances in ADCs - from initial discovery to approved drug. He is also the executive editor of Onco'Zine and a co-host of The Onco'Zine Brief, a radio/podcast show made for public radio.