Duvelisib Demonstrates an Acceptable Safety
Profile in Combination with Romidepsin or Bortezomib in Patients
with Relapsed/Refractory TCL
Combination of Duvelisib and Romidepsin
Achieves 60% Overall Response Rate Including a 27% Complete
Response Rate in these patient populations
Verastem, Inc. (NASDAQ: VSTM), focused on discovering and
developing drugs to improve the survival and quality of life of
cancer patients, today announced the presentation of new
preclinical and Phase 1 clinical data from an
investigator-sponsored study evaluating the safety and activity of
oral duvelisib in combination with romidepsin (Istodax®) or
bortezomib (Velcade®) in relapsed or refractory T-cell lymphomas
(TCL) at the American Society of Hematology (ASH) 2017 Annual
Meeting held December 9-12, 2017 in Atlanta. Duvelisib is a
first-in-class oral dual inhibitor of phosphoinositide-3-kinase
(PI3K)-delta and PI3K-gamma which is currently being developed for
the treatment of relapsed or refractory Chronic Lymphocytic
Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) and Follicular
Lymphoma (FL). In addition, duvelisib is being studied in other
hematologic malignancies including both peripheral and cutaneous T
cell lymphoma (TCL).
“The data presented today at ASH demonstrate that oral
duvelisib, combined with either romidepsin or bortezomib, has an
acceptable safety profile in patients with relapsed or refractory
TCL with response rates, while still preliminary, that appear
promising when compared to those seen with currently approved
therapies,” said Steven Horwitz, MD, Memorial Sloan Kettering
Cancer Center (MSKCC), co-principal investigator of the Phase 1
study, and lead author of the oral presentation. “We were
especially pleased to see that these response rates were even
higher in patients with peripheral TCL (PTCL), a rare and
aggressive type of non-Hodgkin lymphoma. These clinical results
were further bolstered by important preclinical findings showing
duvelisib’s cell killing activity in vitro and its ability to
promote beneficial changes within the in vivo tumor
microenvironment.”
“The preclinical and Phase 1 results reported today by the team
at MSKCC are important because they provide further validation for
our continued expansion of the duvelisib development program into
T-cell malignancies including PTCL,” said Diep Le, MD, PhD, Chief
Medical Officer of Verastem. “Overall, our data presentations at
ASH this year continue to build upon the strong foundation of
preclinical research and clinical investigation for Verastem’s
product candidates, demonstrating their anti-cancer activity,
either alone or in combination with other agents, across a wide
variety of hematologic malignancies.”
Phase 1 Safety and Activity Results
This multicenter, Phase I trial is comprised of parallel arms
evaluating oral duvelisib in combination with romidepsin (arm A) or
bortezomib (arm B) in patients with relapsed/refractory TCL,
including PTCL and cutaneous T-cell lymphoma (CTCL). Oral duvelisib
was dosed at 25mg, 50mg, or 75mg twice-daily (BID) on days 1-28.
Romidepsin 10mg/m2 was dosed on Days 1, 8, and 15 (arm A) or
bortezomib 1mg/m2 on Days 1, 4, 8, and 11 (arm B), both cohorts on
28-day cycles.
In arm A, there were 15 patients evaluable for efficacy (PTCL,
n=11; CTCL, n=4). Of these, nine responded (4 complete responses
(CR) and 5 partial responses (PR) for an overall response rate
(ORR) of 60%. Seven of the 11 patients with PTCL responded (4 CR
and 3 PR) for an ORR of 64%. Among the 9 patients evaluable for
safety (25mg, n=3; 50mg, n=3; 75mg, n=3), there were no dose
limiting toxicities (DLT), therefore oral duvelisib 75mg BID in
combination with romidepsin 10mg/m2 IV was defined as the maximum
tolerated dose (MTD). The most common Grade 1/2 adverse events were
fatigue (n=9), nausea (n=8), altered taste (n=8) and diarrhea
(n=6), rash (n=5), dysphagia (n=4) and anorexia (n=4). The most
common Grade 3/4 adverse events were neutropenia (n=6),
thrombocytopenia (n=1), lung infection (n=1), pleural effusion
(n=1) and hyponatremia (n=1). There were two deaths (sepsis and
diffuse alveolar hemorrhage following allogeneic stem cell
transplant) that were both assessed as unrelated to study drug.
In arm B, there were 17 patients evaluable for efficacy (PTCL,
n=10; CTCL, n=7). Of these, six responded (3 CRs and 3 PRs) for an
ORR of 35%. Five of the 10 patients with PTCL responded (3 CRs and
2 PRs) for an ORR of 50%. Among the 14 patients evaluable for
safety (25mg, n=6; 50mg, n=3; 75mg, n=5), there was one DLT
(pneumonia) in the 25mg group. The MTD was determined to be oral
duvelisib 25mg BID in combination with bortezomib 1mg/m2 IV. The
most common Grade 1/2 adverse events were diarrhea/colitis (n=11),
nausea/vomiting (n=4), chills (n=4) and fatigue (n=4). The most
common Grade 3/4 adverse events were ALT and AST elevation (n=6),
rash (n=2) and neutropenia (n=2). There was a case of
Stevens-Johnson syndrome resulting in death which was assessed by
the investigator as possibly related to bortezomib, duvelisib, and
trimethoprim-sulfamethoxazole, a medication that was initiated at
the start of the study.
A copy of this oral presentation will be available here
following the conclusion of the session.
About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular
populations and extracellular matrices within the tumor or cancer
niche that support cancer cell survival. This includes
immunosuppressive cell populations such as regulatory T-cells,
myeloid-derived suppressor cells, M2 TAMS, as well as
tumor-associated fibroblasts and extracellular matrix proteins
which can hamper the entry and therapeutic benefit of cytotoxic
immune cells and anti-cancer drugs. In addition to targeting the
proliferative and survival signaling of cancer cells, Verastem’s
compounds duvelisib and defactinib target the tumor
microenvironment as a mechanism of action to potentially improve a
patient’s response to therapy.
About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of
phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes
known to help support the growth and survival of malignant B-cells
and T-cells. PI3K signaling may lead to the proliferation of
malignant B- and T-cells and is thought to play a role in the
formation and maintenance of the supportive tumor
microenvironment.1,2,3 Duvelisib is currently being evaluated
in late- and mid-stage extension trials, including DUO™, a
randomized, Phase 3 monotherapy study in patients with relapsed or
refractory chronic lymphocytic leukemia (CLL)/small lymphocytic
lymphoma (SLL),4 and DYNAMO™, a single-arm, Phase 2
monotherapy study in patients with refractory indolent non-Hodgkin
lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary
endpoints and Verastem intends to submit a New Drug
Application (NDA) requesting the full approval of duvelisib for the
treatment of patients with relapsed or refractory CLL/SLL, and
accelerated approval for the treatment of patients with relapsed or
refractory follicular lymphoma (FL). Duvelisib is also being
developed by Verastem for the treatment of peripheral
T-cell lymphoma (PTCL), and is being investigated in combination
with other agents through investigator-sponsored studies.6
Information about duvelisib clinical trials can be found
on www.clinicaltrials.gov
About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase
encoded by the PTK-2 gene that is involved in cellular adhesion
and, in cancer, metastatic capability. Defactinib (VS-6063) and
VS-4718 are orally available compounds that are potent inhibitors
of FAK. Defactinib and VS-4718 utilize a multi-faceted approach to
treat cancer by reducing cancer stem cells, enhancing anti-tumor
immunity, and modulating the local tumor microenvironment.
Defactinib is currently being studied in multiple clinical trials
for patients with cancer.
About Verastem, Inc.
Verastem, Inc. (NASDAQ:VSTM) is a biopharmaceutical company
focused on discovering and developing drugs to improve outcomes for
patients with cancer. Verastem is currently developing duvelisib, a
dual inhibitor of PI3K-delta and PI3K-gamma, which has successfully
met its primary endpoint in a Phase 2 study in iNHL and a Phase 3
clinical trial in patients with CLL/SLL. In addition, Verastem is
developing the FAK inhibitor defactinib, which is currently being
evaluated in three separate clinical collaborations in combination
with immunotherapeutic agents for the treatment of several
different cancer types, including pancreatic cancer, ovarian
cancer, non-small cell lung cancer, and mesothelioma. Verastem’s
product candidates seek to treat cancer by modulating the local
tumor microenvironment, enhancing anti-tumor immunity, and reducing
cancer stem cells. For more information, please visit
www.verastem.com.
Verastem, Inc. forward-looking statements notice:
This press release includes forward-looking statements about
Verastem's strategy, future plans and prospects, including
statements regarding the development and activity of Verastem's
investigational product candidates, including duvelisib and
defactinib, and Verastem's PI3K and FAK programs generally, the
structure of our planned and pending clinical trials and the
timeline and indications for clinical development and regulatory
submissions. The words "anticipate," "believe," "estimate,"
"expect," "intend," "may," "plan," "predict," "project," "target,"
"potential," "will," "would," "could," "should," "continue," and
similar expressions are intended to identify forward-looking
statements, although not all forward-looking statements contain
these identifying words. Each forward-looking statement is subject
to risks and uncertainties that could cause actual results to
differ materially from those expressed or implied in such
statement. Applicable risks and uncertainties include the risks
that the preclinical testing of Verastem's product candidates and
preliminary or interim data from clinical trials may not be
predictive of the results or success of ongoing or later clinical
trials; that the full data from the DUO study will not be
consistent with the previously presented results of the study; that
data may not be available when expected, including for the Phase 3
DUO™ study; that even if data from clinical trials is positive,
regulatory authorities may require additional studies for approval
and the product may not prove to be safe and effective; that the
degree of market acceptance of product candidates, if approved, may
be lower than expected; that the timing, scope and rate of
reimbursement for our product candidates is uncertain; that there
may be competitive developments affecting our product candidates;
that data may not be available when expected; that enrollment of
clinical trials may take longer than expected; that our product
candidates will cause unexpected safety events or result in an
unmanageable safety profile as compared to their level of efficacy;
that duvelisib will be ineffective at treating patients with
lymphoid malignancies; that Verastem will be unable to successfully
initiate or complete the clinical development of its product
candidates; that the development of Verastem's product candidates
will take longer or cost more than planned; that Verastem may not
have sufficient cash to fund its contemplated operations; that
Verastem or Infinity Pharmaceuticals, Inc. (Infinity) will fail to
fully perform under the duvelisib license agreement; that Verastem
may be unable to make additional draws under its debt facility or
obtain adequate financing in the future through product licensing,
co-promotional arrangements, public or private equity, debt
financing or otherwise; that Verastem will not pursue or submit
regulatory filings for its product candidates, including for
duvelisib in patients with CLL or iNHL; and that Verastem's product
candidates will not receive regulatory approval, become
commercially successful products, or result in new treatment
options being offered to patients. Other risks and uncertainties
include those identified under the heading "Risk Factors" in
Verastem's Annual Report on Form 10-K for the year ended December
31, 2016 and in any subsequent filings with the U.S. Securities and
Exchange Commission. The forward-looking statements contained in
this press release reflect Verastem's views as of the date of this
release, and Verastem does not undertake and specifically disclaims
any obligation to update any forward-looking statements.
References
1 Winkler et al. PI3K-delta and PI3K-gamma inhibition by IPI-145
abrogates immune responses and suppresses activity in autoimmune
and inflammatory disease models. Chem Biol 2013; 20:1-11.
2 Reif et al. Cutting Edge: Differential roles for
phosphoinositide 3 kinases, p110-gamma and p110-delta, in
lymphocyte chemotaxis and homing. J Immunol 2004:173:2236-2240.
3 Schmid et al. Receptor tyrosine kinases and TLR/IL1Rs
unexpectedly activate myeloid cell PI3K, a single convergent point
promoting tumor inflammation and progression. Cancer Cell
2011;19:715-727.
4 www.clinicaltrials.gov, NCT02004522
5 www.clinicaltrials.gov, NCT01882803
6 www.clinicaltrials.gov, NCT02783625, NCT02158091
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version on businesswire.com: http://www.businesswire.com/news/home/20171211006011/en/
Verastem, Inc.Brian Sullivan, 781-292-4214Senior Director,
Corporate Developmentbsullivan@verastem.com
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