SYDNEY, June 15, 2021 /PRNewswire/ -- Kazia Therapeutics
Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug
development company, is pleased to announce that it has entered a
collaboration with the Joan & Sanford I
Weill Medical College of Cornell University in the United States, to launch a phase II
clinical study investigating the use of Kazia's investigational new
drug, paxalisib, in combination with ketogenesis, for
glioblastoma.
Key Points
- Research by Professor Lew
Cantley, who discovered the PI3K pathway, suggests that
ketogenesis may enhance the activity of PI3K inhibitors in
glioblastoma, with impressive preclinical data previously published
in Nature
- Ketogenesis represents an alternative biochemical mechanism in
which the body is fueled by fats and proteins rather than by
glucose; it occurs in states such as starvation, and also in
response to a 'ketogenic diet'
- Data from this study has the potential to significantly enhance
the activity of paxalisib in glioblastoma, and to minimize certain
side effects, including hyperglycemia (high blood sugar)
- Dr Howard Fine, founding
Director of the Brain Tumor Center at New York-Presbyterian Weill
Cornell Medical Center, will serve as Principal Investigator;
Professor Cantley will be a scientific advisor to the study
- Kazia will provide support including study drug and a financial
grant
Dr Fine, Principal Investigator to the study, commented,
"glioblastoma remains an immensely challenging disease, and we need
the most potent array of tools at our disposal in order to treat
it. My lab has extensive experience of translational research in
this area, and I am excited to explore the potential for a
brain-penetrant PI3K inhibitor in combination with
ketogenesis."
Professor Cantley, who is a scientific advisor to the study,
added, "the interplay between the PI3K pathway, insulin signaling,
and tumor growth has been a focus of scientific interest for some
time now. Our research clearly shows the synergistic benefits of
PI3K inhibition and ketosis in animal models of glioblastoma. This
is an important project, designed to verify these laboratory
findings in the human setting."
Ketogenesis and Glioblastoma
Cells in the human body generally rely on glucose as 'fuel' for
their energy requirements. However, when glucose is not readily
available, cells can metabolise fats and proteins to provide
energy. The fats and proteins are broken down to an intermediate
form known as ketones, and so this biochemical pathway is referred
to as 'ketogenesis'.
Unlike healthy cells, most tumour cells are poorly able to
metabolise ketones, and so depend on glucose for their energy
needs. Consequently, many researchers have experimented with
'ketogenic diets' as a potential treatment for
cancer.[1]
In addition, scientists in Professor Cantley's lab have shown
that insulin has the potential to counteract the anti-tumor effects
of PI3K inhibitors.[2] Insulin is a hormone produced by
the body in response to high levels of glucose. When the body is in
a state of ketosis, glucose is absent, and so insulin falls to very
low levels.
For these reasons, there is a sound rationale to explore a
combination of ketogenic diet and paxalisib in glioblastoma. In
this study, patients will also receive metformin, a common
anti-diabetic drug, which will help to further lower insulin
levels.
[1] A Kapelner
& M Vorsanger (2015). Medical Hypotheses.
84(3):162-168
[2] B Hopkins et
al. (2018). Nature. 560:499-503
|
Clinical Trial Design
This study will comprise two arms. The first will contain
patients with newly diagnosed glioblastoma who have unmethylated
MGMT promotor status. These patients are essentially resistant to
temozolomide, the existing standard-of-care therapy. The second arm
will contain patients with recurrent disease, who have progressed
after taking standard-of-care therapy.
In each arm, paxalisib will be combined with metformin and with
a ketogenic diet. The diet will be overseen by expert clinical
dieticians to ensure that it is scientifically appropriate and that
patients are compliant.
An initial cohort of approximately sixteen patients will be
recruited to each arm. If there are signals of activity in a given
arm, that arm will be expanded to approximately thirty patients.
The primary endpoint will be progression-free survival at six
months (PFS6). In addition to efficacy and safety, the study will
examine a range of metabolic and pharmacodynamic biomarkers to help
inform future research and clinical practice. The study is expected
to take approximately two years to complete.
Dr Howard Fine will serve as
Principal Investigator to the study. Dr Fine is the founding
Director of the Brain Tumor Center at New York-Presbyterian Weill
Cornell Medical Center, and Associate Director for Translational
Research at the Sandra and Edward Meyer Cancer Center at Weill
Cornell Medicine. He is an internationally recognized leader in the
field of neuro-oncology, with more than 30 years of experience in
both laboratory and clinical research as well as in the care of
patients with brain tumors. Dr Fine has built large
multidisciplinary brain tumor programs at top academic institutions
such as the Dana Farber Cancer Institute / Harvard Medical School and the National Institutes
of Health, has cared for nearly 20,000 patients with brain and
spinal cord tumors in his career, has conducted over 100 clinical
trials, published over 250 papers and book chapters on brain
tumors, and for over two decades has run a continuously operating
translational genetic / molecular laboratory devoted to a better
understanding of, and better therapies for, brain tumors.
Weill Cornell Medical Center
The Joan & Sanford I. Weill Medical
College of Cornell University, known generally as Weill
Cornell Medicine, and based in New York,
NY, is the medical school of Cornell
University, and is one of the leading medical research
centers in the United States. Its
notable alumni include Dr Anthony
Fauci, director of the National Institute of Allergy and
Infectious Disease.
Paxalisib Clinical Program
The initiation of this trial in glioblastoma brings the number
of ongoing clinical studies of paxalisib in brain cancer to
nine.
Sponsor
|
Phase
|
Indication
|
Registration
|
Kazia
Therapeutics
|
II
|
Glioblastoma
|
NCT03522298
|
Global Coalition
for
Adaptive Research
|
II / III
|
Glioblastoma
|
NCT03970447
|
Weill Cornell
Cancer
Center
|
II
|
Glioblastoma
(with ketogenic diet + metformin)
|
TBD
|
Alliance for Clinical
Trials
in Oncology
|
II
|
Brain
metastases
|
NCT03994796
|
Dana-Farber
Cancer
Institute
|
II
|
Breast cancer brain
metastases
(with
Herceptin)
|
NCT03765983
|
Dana-Farber
Cancer
Institute
|
II
|
Primary CNS
lymphoma
|
NCT04906096
|
Pacific Pediatric
Neuro-
Oncology Consortium
|
N/A
|
DIPG &
DMGs
|
TBD
|
St Jude
Children's
Research Hospital
|
I
|
DIPG (childhood brain
cancer)
|
NCT03696355
|
Memorial Sloan
Kettering Cancer Center
|
I
|
Brain
metastases
(with
radiotherapy)
|
NCT04192981
|
Next Steps
Recruitment to this study is expected to commence by the end of
CY2021, subject to approval by Institutional Review Boards, FDA,
and other authorities.
About Kazia Therapeutics Limited
Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA) is an
oncology-focused drug development company, based in Sydney, Australia.
Our lead program is paxalisib, a brain-penetrant inhibitor of
the PI3K / Akt / mTOR pathway, which is being developed to treat
glioblastoma, the most common and most aggressive form of primary
brain cancer in adults. Licensed from Genentech in late 2016,
paxalisib commenced recruitment to GBM AGILE, a pivotal study in
glioblastoma, in January 2021. Eight
additional studies are active in various forms of brain cancer.
Paxalisib was granted Orphan Drug Designation for glioblastoma by
the US FDA in February 2018, and Fast
Track Designation for glioblastoma by the US FDA in August 2020. In addition, paxalisib was granted
Rare Pediatric Disease Designation and Orphan Designation by the US
FDA for DIPG in August 2020.
Kazia is also developing EVT801, a small-molecule inhibitor of
VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to
be active against a broad range of tumour types and has provided
compelling evidence of synergy with immuno-oncology agents. A phase
I study is expected to begin in CY2021.
For more information, please visit www.kaziatherapeutics.com or
follow us on Twitter @KaziaTx.
This document was authorized for release to the ASX by
James Garner, Chief Executive
Officer, Managing Director.
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