CAMBRIDGE, Mass., Dec. 14, 2018 /PRNewswire/ -- Leap Therapeutics,
Inc. (NASDAQ:LPTX) today presented clinical data from its ongoing
Phase I/II study of TRX518 in combination with gemcitabine,
KeytrudaÒ (pembrolizumab), or OpdivoÒ (nivolumab) in
patients with advanced solid tumors at the European Society for
Molecular Oncology (ESMO) Immuno-Oncology Congress 2018. In
addition, Leap provided the top-line final data from the Phase I/II
study of DKN-01 in combination with gemcitabine and cisplatin
chemotherapy in patients with advanced biliary tract cancer.
Leap will host a conference call and webcast on Monday, December 17, 2018 at 8:30 AM US Eastern Time with Jason J. Luke, MD, Assistant Professor of
Medicine, Pritzker School of Medicine at the University of Chicago and Todd M. Bauer, MD, Sarah Cannon Research
Institute/Tennessee Oncology PLLC, TN. Drs. Luke and Bauer
will discuss patient outcomes and provide additional perspectives
about the TRX518 program.
TRX518
TRX518 is unique among Glucocorticoid-Induced TNF Receptor
(GITR) agonist antibodies for its aglycosyl design, permitting
activation of GITR signaling without depleting CD8+ T-effector
cells. In cancer patients, TRX518 has been shown to increase
CD8+ T-effector cell infiltrate and the expression of granzyme B,
as well as decrease CD4+ T-regulatory cell infiltrate. The dual
function of TRX518 is designed to enhance the anti-tumor activity
of chemotherapies and immune checkpoint inhibitors, such as
anti-PD-1/PD-L1 antibodies.
TRX518 Clinical Data Presented at ESMO Immuno-Oncology
Congress 2018
The clinical trial is a continuation of the TRX518 multi-dose
monotherapy study that has been expanded with three combination
study arms to evaluate lower (2 mg/kg loading dose with 1 mg/kg
maintenance doses) and higher (4 mg/kg loading dose with 1 mg/kg
maintenance doses) dose levels of TRX518 in combination with
gemcitabine chemotherapy or Keytruda or Opdivo anti-PD-1 immune
checkpoint antibodies.
Key Findings:
- In monotherapy and combination studies, TRX518 demonstrated
safety, tolerability, and clinical benefit in patients with heavily
pretreated solid tumors.
- TRX518 in combination with Keytruda or Opdivo achieved durable
complete and partial responses in patients not expected to respond
to anti-PD-1 therapy alone, including a confirmed complete response
in an esophageal squamous cell cancer patient and a confirmed
partial response in an anti-PD-1 refractory urothelial cancer
patient.
- TRX518 in combination with gemcitabine achieved meaningful
clinical benefit and objective tumor reduction for heavily
pretreated patients suffering from pancreatic, biliary tract,
mesothelioma, appendiceal, and ovarian cancer.
- The biopsies of responding patients demonstrated an increase in
CD8+ T-effector cells and granzyme B expression and a reduction in
CD4+ T-regulatory cells and FoxP3 expression, hallmarks of immune
activation and anti-tumor activity associated with GITR
agonism.
TRX518/gemcitabine combination:
The combination arm evaluating TRX518 in combination with
gemcitabine enrolled thirty patients who had received one to nine
prior therapies. Four patients were treated at the lower dose of
TRX518, and twenty-six patients were treated at the higher dose.
The study enrolled fourteen patients with pancreatic cancer, five
with biliary tract cancer, and eleven with other cancers including
ovarian, appendiceal, and mesothelioma. Seventeen patients had
previously progressed on gemcitabine therapy, and ten had
previously progressed on anti-PD-1/PD-L1 therapy.
Clinical outcomes data as of December 5,
2018 includes:
TRX518 +
gemcitabine
|
N
|
Response
Evaluable
|
Stable
Disease
|
Progressive
Disease
|
Disease Control Rate
(Response Evaluable)
|
Overall
|
30
|
25
|
13
|
12
|
52%
|
Lower dose
TRX518
|
4
|
2
|
0
|
2
|
0%
|
Higher dose
TRX518
|
26
|
23
|
13
|
10
|
56.5%
|
|
|
|
|
|
|
Pancreatic
Cancer
|
14
|
10
|
5
|
5
|
50%
|
Biliary Tract Cancer
(BTC)
|
5
|
5
|
4
|
1
|
80%
|
Other
Cancers
|
11
|
10
|
4
|
6
|
40%
|
|
|
|
|
|
|
Nineteen pancreatic or biliary tract cancer (PBC) patients were
enrolled, and nine remain on study. Nearly all of these patients
had received prior gemcitabine therapy, and nine (47%) remained on
study for more than four cycles. Eight (67%) of twelve evaluable
PBC patients previously treated with gemcitabine who received the
higher dose of TRX518 have had stable disease, including a
fourth-line pancreatic cancer patient who remains on study in Cycle
9 with a 21% reduction in tumor burden. Pancreatic cancer patients
who have progressed on gemcitabine have extremely poor outcomes
with studies indicating a range of 1.6 to 2.9 months between median
progression and median overall survival.
Additional reductions in tumor burden and durable clinical
benefit have been noted in appendiceal cancer (-4% in Cycle 7),
mesothelioma (-5% in Cycle 6), and two in ovarian cancer (-15% in
Cycle 5, -9% off after 4 cycles).
TRX518/Keytruda or Opdivo combination
The combination arms evaluating TRX518 in combination with
Keytruda or Opdivo enrolled fourteen patients in the dose
escalation cohorts as of December 5,
2018. Both patients treated with the higher dose of TRX518
plus Keytruda have had clinical benefit. An esophageal squamous
cell carcinoma patient has had a confirmed complete response, which
remains ongoing for seven months, and an ocular melanoma patient
has had a 23% reduction in tumor volume and six months of ongoing
stable disease. In the low dose TRX518 plus Opdivo combination arm,
a patient with urothelial carcinoma who had failed prior Keytruda
had a confirmed partial response and remained on therapy for six
months.
Enrollment is now complete in the dose escalation cohort for
TRX518 and Keytruda and continues in the high dose escalation
cohort of TRX518 and Opdivo. Leap anticipates that dose expansion
cohorts for both combinations will initiate in the first quarter
2019.
DKN-01
DKN-01 is a humanized monoclonal antibody targeting the
Dickkopf-1 (DKK1) protein, a Wnt
pathway modulator. DKN-01 is in clinical trials in patients with
esophagogastric cancer, hepatobiliary cancer, and gynecologic
cancers.
At the Society for Immunotherapy of Cancer 33rd
Annual Meeting, Leap announced that the combination of DKN-01 and
paclitaxel generated a 46.7% overall response rate, 19.6 weeks
median progression free survival, and 61.1 weeks median overall
survival in fifteen evaluable esophagogastric cancer patients as a
second-line therapy. In the subgroup of twelve evaluable patients
with heavily pre-treated esophageal squamous cell carcinoma, DKN-01
and paclitaxel produced a 33.3% overall response rate, 13.7 weeks
median progression free survival, and 31.0 weeks median overall
survival.
At the ESMO 2018 Annual Meeting, Leap announced that the
combination of DKN-01 and Keytruda demonstrated promising clinical
activity with a 23.5% overall response rate and 58.8% disease
control rate in evaluable gastric or gastroesophageal junction
cancer patients who have been heavily pretreated and have not had
prior anti-PD-1/PD-L1 therapy. The combination has generated
durable responses in subgroups less likely to respond to
pembrolizumab monotherapy, for example, patients whose tumors are
microsatellite stable and/or PD-L1 negative. Additional data from
the DKN-01/Keytruda combination is expected in the second quarter
of 2019.
DKN-01 in combination with gemcitabine and cisplatin in
Advanced Biliary Tract Cancer
The open-label, Phase I/II study enrolled fifty-one patients
with advanced biliary tract cancer (BTC). Seven patients received
one of two dose levels (150 mg or 300 mg) of DKN-01 in combination
with gemcitabine and cisplatin during Part A, with forty-four
additional patients treated at the 300 mg dose level of DKN-01 in
the Part B expansion cohort. Forty-two patients were chemotherapy
treatment-naïve, and nine patients had received 1-2 prior
therapies. The primary objective of this study was to evaluate the
safety, pharmacokinetics, and efficacy of DKN-01 in combination
with gemcitabine and cisplatin.
In the study, DKN-01 in combination with gemcitabine and
cisplatin was well tolerated with no new emerging safety trends.
Forty-seven patients overall were treated at the 300 mg DKN-01 dose
level, and their median overall survival was 53.7 weeks (12.4
months). Median progression free survival was 37.7 weeks (8.7
months). Ten patients (21.3%) had a partial response and thirty-one
patients (66.0%) experienced a best response of stable disease,
representing a disease control rate of 87.2%. Two patients (4.3%)
had progressive disease, and four patients (8.5%) were
non-evaluable for response. The one-year probability of overall
survival was 0.51, and the six-month probability of progression
free survival was 0.58. The median number of cycles of DKN-01 was
seven (range of 1 to 23), and the median duration on study was 331
days.
"Patients with metastatic biliary tract cancer have a poor
prognosis with an unmet medical need, with median overall survival
of less than one year. We are very pleased by the progression-free
survival, overall survival, and favorable safety profile
demonstrated by DKN-01 in combination with gemcitabine and
cisplatin in this single arm study," commented by Andrew X. Zhu, M.D., Director of Liver Cancer
Research at Massachusetts General Hospital Cancer Center and
Professor of Medicine at Harvard Medical
School. "The activity of DKN-01 in biliary tract cancer
warrants further development in the front-line setting as well as
in second-line in combination with anti-PD-1/PD-L1 antibodies."
TRX518 Clinical Perspectives Conference Call and
Webcast
On Monday, December 17, 2018 at
8:30AM ET, Leap will be hosting a
conference call and webcast for the investment community. To access
the conference call, please dial (866) 589-0108 (US/Canada
Toll-Free) or (409) 231-2048 (international) and refer to
conference ID 9187987. The presentation will also be webcast live
and will be available on Leap's website,
https://www.leaptx.com/program-webcastshttps://edge.media-server.com/m6/p/28e7k6ei.
A replay of the webcast will be available on Leap's website after
the event and will be available for a limited time.
About Leap Therapeutics
Leap Therapeutics (NASDAQ:LPTX) is focused on developing
targeted and immuno-oncology therapeutics. Leap's most advanced
clinical candidate, DKN-01, is a humanized monoclonal antibody
targeting the Dickkopf-1 (DKK1)
protein, a Wnt pathway modulator. DKN-01 is in clinical trials in
patients with esophagogastric cancer, biliary tract cancer, and
gynecologic cancers, with an emerging focus on patients with
defined mutations of the Wnt pathway and in combination with immune
checkpoint inhibitors. Leap's second clinical candidate, TRX518, is
a humanized GITR agonist monoclonal antibody designed to enhance
the immune system's anti- tumor response that is in two advanced
solid tumor studies. For more information about Leap Therapeutics,
visit http://www.leaptx.com or our public filings with the SEC
that are available via EDGAR at http://www.sec.gov.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc. OPDIVO® is a
registered trademark of Bristol-Myers Squibb Company.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within
the meaning of Section 27A of the Securities Act of 1933, Section
21E of the Securities Exchange Act of 1934 and the Private
Securities Litigation Reform Act of 1995, which involve risks and
uncertainties. These statements include statements regarding Leap's
expectations with respect to the development and advancement of
DKN-01 and TRX518, including the initiation, timing, design and
results of future studies, enrollment in future studies, business
development, and other future expectations, plans and prospects.
Although Leap believes that the expectations reflected in such
forward-looking statements are reasonable as of the date made,
forward-looking statements are subject to known and unknown risks,
uncertainties and other factors that could cause actual results to
differ materially from our expectations. Such risks and
uncertainties include, but are not limited to: the outcome, cost,
and timing of our product development activities and clinical
trials; the uncertain clinical development process, including the
risk that clinical trials may not have an effective design or
generate positive results; our ability to obtain and maintain
regulatory approval of our drug product candidates; our plans to
research, develop, and commercialize our drug product candidates;
our ability to achieve market acceptance of our drug product
candidates; unanticipated costs or delays in research, development,
and commercialization efforts; the applicability of clinical study
results to actual outcomes; the size and growth potential of the
markets for our drug product candidates; our ability to continue
obtaining and maintaining intellectual property protection for our
drug product candidates; and other risks. Detailed information
regarding factors that may cause actual results to differ
materially will be included in Leap Therapeutics' periodic filings
with the Securities and Exchange Commission (the "SEC"), including
Leap Therapeutics' Form 10-K that Leap filed with the SEC on
February 23, 2018. Any
forward-looking statements contained in this release speak only as
of its date. We undertake no obligation to update any forward-
looking statements contained in this release to reflect events or
circumstances occurring after its date or to reflect the occurrence
of unanticipated events.
CONTACT:
Leap Therapeutics, Inc.
Douglas E. Onsi
Chief Financial Officer
donsi@leaptx.com
617-714-0360
Argot Partners
Investor Relations
Heather Savelle or Mary Jenkins
212-600-1902
heather@argotpartners.com
mary@argotpartners.com
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