Poster presentation at
American Association for Cancer
Research
(AACR) Annual Meeting 2016
New Orleans, Louisiana, USA
April 16 - 20, 2016
Dr Kimberley Lilischkis BSc, PhD, MBA
Clinical and Regulatory Affairs Director, Novogen Limited
‘Preclinical toxicology of TRXE-002-1, Cantrixil’
Kimberley Lilischkis1, Andrew Heaton1, Ayesha Alvero2, Gil Mor2, David M. Brown1
1
Novogen Pty Ltd, Hornsby, NSW, 2077 Australia
2
Yale University, New Haven, CT, USA
Introduction:
TRXE-002-1 is a low molecular weight super
benzopyran molecule identified as having potent
activity against many cancer phenotypes. It was
identified from a library of analogues as being able to
induce cell death in both chemoresistant CD44+/
MyD88+ ovarian cancer stem cells (IC50 of ~ 50
nM) and chemosensitive CD44-/MyD88- ovarian
cancer cells, and disrupt spheroid cultures formed
from cancer stem cells. In vivo studies have
confirmed efficacy in a rodent intra-peritoneal model
of human ovarian cancer. Here we report on preclinical toxicology studies conducted on TRXE-002-1.
Method:
We conducted a full GLP dog CV study using a 4x4
Latin Square Crossover study design where we
assessed telemetric ECG recordings from 4 male
dogs post IP administration at doses up to 30 mg/kg.
Thirty seconds of continuous ECG tracings were
collected pre-dose (Baseline) and at 0.5, 1.5, 2.5,
and, 24 hours after test article or vehicle
administration. In addition, TRXE-002-1 was
assessed in standard assays used to identify
mutagenic potential using the bacterial reverse
mutation assay. The potential for TRXE-002-1 to
induce micronuclei in the bone marrow of SPF Arc(S)
Swiss mice was also investigated as a measure of
clastogenicity. TRXE-002-1 toxicology was evaluated
in MTD, and 28-day repeat dose GLP studies in rats
and dogs.
Results:
TRXE-002-1 was found to have no effect on cardiac
parameters
of
blood
pressure
and
electrocardiography in dogs. TRXE-002-1 had no
reverse mutagenic potential using the bacterial
reverse mutation pre-incubation method ± S9
metabolic activation (Salmonella typhimurium strains
TA98, TA100, TA1535, TA1537, and the WP2 uvrA
Escherichia coli strain). Similarly, TRXE-002-1 was
shown to be non-mutagenic using the gene mutation
test at the TK locus in L5178Y mouse lymphoma cell
culture with and without metabolic activation. High
doses of TRXE-002-1 (200 and 400 mg/kg) caused a
significant increase in incidence of micronuclei in
male and female mice. Repeat intraperitoneal
injection of TRXE-002-1 to male and female dogs
and rats over 28 days was well tolerated. Adverse
TRXE-002 1-related effects were limited to
microscopic findings in the testes and epididymides
for male rats and dogs at high doses. Macroscopic
observations at necropsy were confined to sporadic
distention of the cecum and colon and colon
obstruction in rats only (high dose) with no observed
gastrointestinal microscopic findings reported in
either species. Other observations were mostly
resolved after a 14-day recovery period, except
microscopic findings in the testes from both species.
Conclusion:
These data show that TRXE-002-1 has an
acceptable toxicity profile in rats and dogs, and is
without genotoxicity and cardiotoxicity at
clinically relevant concentrations. TRXE-002-1 has
been granted orphan drug status by the U.S. Food
and Drug Administration (FDA) for ovarian cancer
and a first-in-human clinical trial is planned for 2016.
April 2016