SAN DIEGO, Feb. 13, 2020 /PRNewswire/ -- Trovagene,
Inc. (Nasdaq: TROV), a clinical-stage, oncology
therapeutics company developing onvansertib for the treatment of
various cancers including prostate, colorectal, and leukemia, today
announced positive data from its ongoing Phase 2 trial of
onvansertib in combination with Zytiga® (abiraterone – Johnson
& Johnson)/prednisone, all administered orally, for the
treatment of patients with Zytiga®-resistant metastatic
castration-resistant prostate cancer (mCRPC).
The clinical data, featured in a poster presentation today at
the American Society for Clinical Oncology (ASCO) 2020
Genitourinary Cancers Symposium in San
Francisco, further demonstrates the efficacy of onvansertib
in patients who develop resistance to first-line treatment with
Zytiga®. Onvansertib addresses Zytiga® resistance across known
androgen receptor (AR) resistance mechanisms. In patients with AR
alterations, 86% had decreases in PSA levels with the addition of
onvansertib to daily Zytiga®.
"Metastatic castration-resistant prostate cancer is the second
leading cause of cancer-related death among men in the United States, and unfortunately many
patients are in desperate need of new treatment options," said
study principal investigator Dr. David
Einstein, Genitourinary Oncology Program, Beth Israel
Deaconess Medical Center. "These data show that adding onvansertib
to abiraterone in metastatic castration-resistant prostate cancer
patients with an early resistance to abiraterone validates
pre-clinical studies and shows potential as a new therapeutic
option."
"We are very encouraged by the significant decreases in
circulating tumor cells (CTCs) with the addition of onvansertib,
given that these changes in CTCs are an accepted surrogate
prognostic factor for efficacy and survival," said Dr. Mark Erlander, Chief Scientific Officer at
Trovagene. "In addition, observing efficacy in patients that have
tumors exhibiting known mechanisms of resistance to ARS inhibitor,
Zytiga®, suggests that onvansertib's activity could extend to
overcoming resistance to other ARS inhibitors such as
Xtandi® and Erleada®."
Key Presentation Highlights:
Efficacy
- Overall, across both arms (A and B), a 63% (12 of 19) response
(Stable Disease – SD and Partial Response – PR) was observed in
patients evaluable for efficacy (completed 12 weeks of treatment
with onvansertib + Zytiga® (abiraterone)/prednisone); 6
patients have been on treatment for ≥7 months
-
- Arm B (onvansertib dosed daily on days 1-5 in a 14-day
cycle)
-
- 80% (4 of 5) patients had SD at 12 weeks, with 3 patients
achieving the efficacy endpoint (PSA stabilization) and 3 patients
remain on treatment
- 60% (3 of 5) patients have or had progression-free survival of
>7 months
- Arm A (onvansertib dosed daily on days 1-5 in a 21-day
cycle)
-
- 57% (8 of 14) patients had SD or PR at 12 weeks, with 5
patients achieving the efficacy endpoint (PSA stabilization) and 4
patients remain on treatment
- 21% (3 of 14) patients have or had progression-free survival; 2
patients remain on treatment for >1 year
- Onvansertib-induced circulating tumor cell (CTC) decrease is
associated with progression-free survival
-
- CTC count, reported as favorable or unfavorable (<5 versus
≥5 CTC/7.5mL of blood, respectively) is a prognostic factor for
survival in CRPC and the conversion from unfavorable to favorable
is associated with improved survival
- At baseline, 25 (78%) patients had unfavorable CTC count with
median of 19 CTC/7.5mL
- 10 of the unfavorable patients were re-analyzed after 12 weeks
of treatment
-
- 5 (50%) patients had a ≥80% CTC decrease, including 2 AR-V7+
patients
- 4 (40%) patients converted from unfavorable to favorable CTC
level (<5 CTC/7.5mL)
- 3 (30%) patients had no detectable CTC
- Median time on treatment for patients with decrease CTC (n=4)
is 7 months to-date, with 4 patients remaining on treatment
- Conversely, median time on treatment for patients with increase
CTC (n=5) was 5 months, and none of these patients remain on
treatment
- Efficacy observed in patients with Zytiga®-resistant androgen
receptor (AR) alterations
-
- AR mechanisms of resistance to abiraterone include the
expression of the constitutively active AR splice variant AR-V7 and
the AR gain-of function point mutation T878A
- Among the 19 patients who completed the 12-week treatment (Arm
A + B):
-
- 5 patients were AR-V7+ at baseline
- 2 patients had AR T878A mutations at baseline
- Onvansertib showed efficacy in patients with AR alterations
(N=7):
-
- 6 (86%) patients had a decrease in PSA levels with the addition
of onvansertib
- 4 (57%) patients had SD or PR at 12 weeks with 3 (43%) patients
achieving the primary efficacy endpoint
- 3 patients have or had progression-free survival of >7
months, 2 patients remain on treatment
Safety
- Safety lead-in cohort was completed in Arm A at 24
mg/m2 and is ongoing in Arm B at 18
mg/m2
- Most frequent G3/G4 AEs were expected, on-target, reversible
hematological (anemia, neutropenia, thrombocytopenia and
leukopenia), associated with the mechanism of action of
onvansertib
-
- Hematological AEs were reversible and effectively managed by
dose delay, dose reduction and/or growth factor support
- Grade 3 hypophosphatemia was reported in 3 patients, next cycle
treatment was delayed for 2 patients to allow recover
Conclusions
- Overall, across both arms (A and B), a 63% (12 of 19) response
(SD + PR) was observed in patients evaluable for efficacy
(completed 12 weeks of treatment); 6 patients have been on
treatment for ≥7 months
- Onvansertib induced profound CTC decreases in patients with
unfavorable CTC count (>80% decrease in 5 of 10 patients
tested); CTC decrease was associated with prolonged response to
treatment and progression-free survival
- 6 of 7 patients with AR alterations (AR-V7+ or AR T878A) had an
immediate decrease in PSA following onvansertib treatment; efficacy
(SD+PR) was achieved in 57% (4 of 7) patients
- In both arms (A and B) onvansertib in combination with
abiraterone was safe and well-tolerated
- A more continuous dosing schedule (Arm C – onvansertib 12
mg/m2 on days 1-14 of a 21-day cycle) is planned to
evaluate safety and efficacy
- Adding onvansertib to abiraterone in mCRPC patients resistant
to abiraterone (rising PSA) validates pre-clinical studies and
shows promise as a new therapeutic option
About the Phase 2 Trial of Onvansertib in Metastatic
Castration-Resistant Prostate Cancer
The trial is a Phase 2 open-label study of onvansertib in
combination with Zytiga® (abiraterone acetate)/prednisone, all
administered orally, in patients with metastatic
castration-resistant prostate cancer (mCRPC), showing signs of
disease progression demonstrated by two rising PSA values separated
by at least one week, while on Zytiga® (NCT03414034). The primary
efficacy endpoint is the proportion of patients achieving disease
control after 12 weeks of study treatment, as defined by lack of
prostate specific antigen (PSA) progression in patients who are
showing signs of early progressive disease (rise in PSA but
minimally symptomatic or asymptomatic) while currently receiving
abiraterone acetate and prednisone. The trial is being conducted by
Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer
Institute (Dana-Farber), and Massachusetts General Hospital Cancer
Center (MGH). David Einstein, MD,
Genitourinary Oncology Program at BIDMC, is the principal
investigator for the trial.
About Onvansertib
Onvansertib is a first-in-class, third-generation, oral and
highly-selective adenosine triphosphate (ATP) competitive inhibitor
of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is
over-expressed in multiple cancers including leukemias, lymphomas
and solid tumors. Onvansertib targets the PLK1 isoform only (not
PLK2 or PLK3), is orally administered and has a 24-hour half-life
with only mild-to-moderate side effects reported. Trovagene
believes that targeting only PLK1 and having a favorable safety and
tolerability profile, along with an improved dose/scheduling
regimen will significantly improve on the outcome observed in
previous studies with a former panPLK inhibitor in AML.
Onvansertib has demonstrated synergy in preclinical studies with
numerous chemotherapies and targeted therapeutics used to treat
leukemias, lymphomas and solid tumor cancers, including irinotecan,
FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene
believes the combination of onvansertib with other compounds has
the potential to improve clinical efficacy in acute myeloid
leukemia (AML), metastatic castration-resistant prostate cancer
(mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and
triple-negative breast cancer (TNBC), as well as other types of
cancer.
Trovagene has three ongoing clinical trials of onvansertib: A
Phase 2 trial of onvansertib in combination with Zytiga®
(abiraterone acetate)/prednisone in patients with mCRPC who are
showing signs of early progressive disease (rise in PSA but
minimally symptomatic or asymptomatic) while currently receiving
Zytiga® (NCT03414034); a Phase 1b/2
Study of onvansertib in combination with FOLFIRI and
Avastin® for second-line treatment in patients with mCRC with
a KRAS mutation (NCT03829410) and a Phase 1b/2 clinical trial of onvansertib in combination
with low-dose cytarabine or decitabine in patients with relapsed or
refractory AML (NCT03303339). Onvansertib has been granted orphan
drug designation by the FDA in the U.S. and by the EC in the
European Union for the treatment of patients with AML.
Trovagene licensed onvansertib (also known as NMS-1286937 and
PCM-075) from Nerviano Medical Sciences (NMS), the largest
oncology-focused research and development company in Italy, and a leader in protein kinase drug
development. NMS has an excellent track record of licensing
innovative drugs to pharma/biotech companies, including Array
(recently acquired by Pfizer), Ignyta (acquired by Roche) and
Genentech.
About Trovagene, Inc.
Trovagene is a clinical-stage, Precision Cancer
Medicine™ oncology therapeutics company developing drugs that
target cell division (mitosis), for the treatment of various
cancers including leukemias, lymphomas and solid tumors. Trovagene
has intellectual property and proprietary technology that enables
the Company to analyze circulating tumor DNA (ctDNA) and clinically
actionable markers to identify patients most likely to respond to
specific cancer therapies. Trovagene plans to continue to
vertically integrate its tumor genomics technology with the
development of targeted cancer therapeutics. For more
information, please visit https://www.trovageneoncology.com.
Forward-Looking Statements
Certain statements in this press release are forward-looking
within the meaning of the Private Securities Litigation Reform Act
of 1995. These statements may be identified by the use of words
such as "anticipate," "believe," "forecast," "estimated" and
"intend" or other similar terms or expressions that concern
Trovagene's expectations, strategy, plans or intentions. These
forward-looking statements are based on Trovagene's current
expectations and actual results could differ materially.
There are a number of factors that could cause actual events
to differ materially from those indicated by such forward-looking
statements. These factors include, but are not limited to,
our need for additional financing; our ability to continue as a
going concern; clinical trials involve a lengthy and expensive
process with an uncertain outcome, and results of earlier studies
and trials may not be predictive of future trial results; our
clinical trials may be suspended or discontinued due to unexpected
side effects or other safety risks that could preclude approval of
our product candidates; uncertainties of government or third party
payer reimbursement; dependence on key personnel; limited
experience in marketing and sales; substantial competition;
uncertainties of patent protection and litigation;
dependence upon third parties; our ability to develop tests, kits
and systems and the success of those products; regulatory,
financial and business risks related to our international expansion
and risks related to failure to obtain FDA clearances or approvals
and noncompliance with FDA regulations. There are no guarantees
that any of our technology or products will be utilized or prove to
be commercially successful. Additionally, there are no
guarantees that future clinical trials will be completed or
successful or that any precision medicine therapeutics will receive
regulatory approval for any indication or prove to be commercially
successful. Investors should read the risk factors set forth
in Trovagene's Form 10-K for the year ended December 31, 2018,
and other periodic reports filed with the Securities and Exchange
Commission. While the list of factors presented here is
considered representative, no such list should be considered to be
a complete statement of all potential risks and uncertainties.
Unlisted factors may present significant additional obstacles to
the realization of forward-looking statements. Forward-looking
statements included herein are made as of the date hereof, and
Trovagene does not undertake any obligation to update publicly such
statements to reflect subsequent events or circumstances.
Trovagene Oncology Contact:
Vicki Kelemen
VP, Clinical Development and Investor Relations
858-952-7652
vkelemen@trovagene.com
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