Steven Horwitz, MD, Gives Oral Presentation
Highlighting Phase 1 Duvelisib Data in Patients with Relapsed or
Refractory PTCL
Data from Two Phase 1 Studies Show Response
Rates of 44-57%, Including Complete Response Rates of 15-22%
Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company),
a biopharmaceutical company focused on developing and
commercializing medicines seeking to improve the survival and
quality of life of cancer patients, today announced an oral
presentation highlighting supportive Phase 1 clinical data for
duvelisib (COPIKTRA™) in patients with relapsed or refractory
peripheral T-cell lymphoma (PTCL) at the 2019 International
Conference on Malignant Lymphoma (ICML) being held June 18-22,
2019, in Lugano, Switzerland. Verastem Oncology is currently
investigating the safety and efficacy of duvelisib monotherapy in
the Phase 2 clinical trial PRIMO in patients with histologically
confirmed relapsed or refractory PTCL.
“Patients with relapsed or refractory PTCL who were treated with
duvelisib demonstrated preliminary, but compelling clinical
activity,” said Steven Horwitz, MD, Memorial Sloan Kettering Cancer
Center, co-principal investigator of the Phase 1 and 2 studies, and
lead author of the oral presentation. “Although the patient numbers
are small in these two Phase 1 studies, we see a positive trend in
response rates. The goal of the ongoing Phase 2 PRIMO study is to
provide guidance on a duvelisib monotherapy dosing regimen in
patients with relapsed or refractory PTCL and to further
characterize its efficacy and tolerability in this population.”
Duvelisib, a targeted oral inhibitor of phosphoinositide
3-kinase (PI3K), and the first approved dual inhibitor of
PI3K-delta and PI3K-gamma, received approval from the U.S. Food and
Drug Administration (FDA) for the treatment of patients with
relapsed or refractory chronic lymphocytic leukemia/small
lymphocytic lymphoma after at least two prior therapies in
September 2018.
Summary of Phase 1 Experience with Duvelisib in PTCL and
Rationale for Phase 2
Relapsed or refractory PTCL is associated with a poor prognosis,
with most therapies inducing responses in less than 30% of patients
and median progression-free survival (PFS) less than 6 months. In
this presentation, researchers summarized the safety and activity
of duvelisib in patients with relapsed or refractory PTCL from two
Phase 1 studies. In the first Phase 1 study, patients (n=13)
received duvelisib until disease progression or intolerance as part
of a dose-escalation phase. In the other Phase 1 study, patients
(n=16) received duvelisib monotherapy 25mg or 75mg twice daily for
one month as a lead-in to a combination regimen with romidepsin or
bortezomib.
Across both studies, a total of 29 patients received duvelisib
at 25mg or 75mg twice daily. Among patients who received duvelisib
75mg dosed twice daily as monotherapy or lead-in monotherapy before
romidepsin, the ORR was 54% and 44%, respectively, with complete
response (CR) rates of 15% to 22%, respectively. Notably, the
overall response rate was 57% among patients receiving duvelisib
25mg twice daily as lead-in monotherapy before bortezomib. The
responses reported here of patients receiving duvelisib as a
lead-in monotherapy experienced these responses at the end of cycle
1. In the phase 1 dose-escalation study, median progression-free
survival was 8.3 months and median overall survival was 16.2
months. In this same study, response to duvelisib typically
occurred by the first assessment (cycle 2) and was observed across
a spectrum of PTCL subtypes. The preliminary safety profile of
duvelisib in patients with relapsed or refractory PTCL was
considered reasonable and consistent with prior studies.
A PDF copy of this oral presentation is available on
www.lymphcon.ch.
Details for the ICML 2019 oral presentation are as
follows:
Title: Duvelisib, an oral dual PI3K-δ,γ inhibitor,
efficacy and safety in patients with relapsed or refractory (RR)
peripheral T-cell lymphoma: rationale for the phase 2 PRIMO trial
Lead author: Steven Horwitz, Memorial Sloan Kettering Cancer
Center Abstract #: 033 Session: Focus On: Results
from Single-Agent Trials Location: Auditorium (USI
Università)
About COPIKTRA™ (duvelisib)
COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase
(PI3K), and the first approved dual inhibitor of PI3K-delta and
PI3K-gamma, two enzymes known to help support the growth and
survival of malignant B-cells. PI3K signaling may lead to the
proliferation of malignant B-cells and is thought to play a role in
the formation and maintenance of the supportive tumor
microenvironment.1,2,3 COPIKTRA is indicated for the treatment of
adult patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two
prior therapies and relapsed or refractory follicular lymphoma (FL)
after at least two prior systemic therapies. COPIKTRA is also being
developed by Verastem Oncology for the treatment of peripheral
T-cell lymphoma (PTCL), for which it has received Fast Track
status, and is being investigated in combination with other agents
through investigator-sponsored studies.4 For more information on
COPIKTRA, please visit www.COPIKTRA.com. Information about
duvelisib clinical trials can be found on
www.clinicaltrials.gov.
Important Safety Information
WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR
COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS
See full prescribing information for complete boxed warning
- Fatal and/or serious infections occurred in 31% of
COPIKTRA-treated patients. Monitor for signs and symptoms of
infection. Withhold COPIKTRA if infection is suspected.
- Fatal and/or serious diarrhea or colitis occurred in 18% of
COPIKTRA-treated patients. Monitor for the development of severe
diarrhea or colitis. Withhold COPIKTRA.
- Fatal and/or serious cutaneous reactions occurred in 5% of
COPIKTRA-treated patients. Withhold COPIKTRA.
- Fatal and/or serious pneumonitis occurred in 5% of
COPIKTRA-treated patients. Monitor for pulmonary symptoms and
interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS
Infections: Serious, including fatal (18/442; 4%),
infections occurred in 31% of patients receiving COPIKTRA 25 mg BID
(N=442). The most common serious infections were pneumonia, sepsis,
and lower respiratory infections. Median time to onset of any grade
infection was 3 months (range: 1 day to 32 months), with 75% of
cases occurring within 6 months. Treat infections prior to
initiation of COPIKTRA. Advise patients to report new or worsening
signs and symptoms of infection. For grade 3 or higher infection,
withhold COPIKTRA until infection has resolved. Resume COPIKTRA at
the same or reduced dose.
Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP)
occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for
PJP during treatment with COPIKTRA and following completion of
treatment with COPIKTRA until the absolute CD4+ T cell count is
greater than 200 cells/μL. Withhold COPIKTRA in patients with
suspected PJP of any grade, and permanently discontinue if PJP is
confirmed.
Cytomegalovirus (CMV) reactivation/infection occurred in 1% of
patients taking COPIKTRA. Consider prophylactic antivirals during
COPIKTRA treatment to prevent CMV infection including CMV
reactivation. For clinical CMV infection or viremia, withhold
COPIKTRA until infection or viremia resolves. If COPIKTRA is
resumed, administer the same or reduced dose and monitor patients
for CMV reactivation by PCR or antigen test at least monthly.
Diarrhea or Colitis: Serious, including fatal (1/442;
<1%), diarrhea or colitis occurred in 18% of patients receiving
COPIKTRA 25 mg BID (N=442). Median time to onset of any grade
diarrhea or colitis was 4 months (range: 1 day to 33 months), with
75% of cases occurring by 8 months. The median event duration was
0.5 months (range: 1 day to 29 months; 75th percentile: 1
month).
Advise patients to report any new or worsening diarrhea. For
patients presenting with mild or moderate diarrhea (Grade 1-2)
(i.e., up to 6 stools per day over baseline) or asymptomatic (Grade
1) colitis, initiate supportive care with antidiarrheal agents,
continue COPIKTRA at the current dose, and monitor the patient at
least weekly until the event resolves. If the diarrhea is
unresponsive to antidiarrheal therapy, withhold COPIKTRA and
initiate supportive therapy with enteric acting steroids (e.g.,
budesonide). Monitor the patient at least weekly. Upon resolution
of the diarrhea, consider restarting COPIKTRA at a reduced
dose.
For patients presenting with abdominal pain, stool with mucus or
blood, change in bowel habits, peritoneal signs, or with severe
diarrhea (Grade 3) (i.e., > 6 stools per day over baseline),
withhold COPIKTRA and initiate supportive therapy with enteric
acting steroids (e.g., budesonide) or systemic steroids. A
diagnostic work-up to determine etiology, including colonoscopy,
should be performed. Monitor at least weekly. Upon resolution of
the diarrhea or colitis, restart COPIKTRA at a reduced dose. For
recurrent Grade 3 diarrhea or recurrent colitis of any grade,
discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening
diarrhea or colitis.
Cutaneous Reactions: Serious, including fatal (2/442;
<1%), cutaneous reactions occurred in 5% of patients receiving
COPIKTRA 25 mg BID (N=442). Fatal cases included drug reaction with
eosinophilia and systemic symptoms (DRESS) and toxic epidermal
necrolysis (TEN). Median time to onset of any grade cutaneous
reaction was 3 months (range: 1 day to 29 months, 75th percentile:
6 months) with a median event duration of 1 month (range: 1 day to
37 months, 75th percentile: 2 months).
Presenting features for the serious events were primarily
described as pruritic, erythematous, or maculo-papular. Less common
presenting features include exanthem, desquamation, erythroderma,
skin exfoliation, keratinocyte necrosis, and papular rash. Advise
patients to report new or worsening cutaneous reactions. Review all
concomitant medications and discontinue any medications potentially
contributing to the event. For patients presenting with mild or
moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA at the
current dose, initiate supportive care with emollients,
antihistamines (for pruritus), or topical steroids, and monitor the
patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous
reaction until resolution. Initiate supportive care with steroids
(topical or systemic) or antihistamines (for pruritus). Monitor at
least weekly until resolved. Upon resolution of the event, restart
COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe
cutaneous reaction does not improve, worsens, or recurs. For
life-threatening cutaneous reactions, discontinue COPIKTRA. In
patients with SJS, TEN, or DRESS of any grade, discontinue
COPIKTRA.
Pneumonitis: Serious, including fatal (1/442; <1%),
pneumonitis without an apparent infectious cause occurred in 5% of
patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset
of any grade pneumonitis was 4 months (range: 9 days to 27 months),
with 75% of cases occurring within 9 months. The median event
duration was 1 month, with 75% of cases resolving by 2 months.
Withhold COPIKTRA in patients with new or progressive pulmonary
signs and symptoms such as cough, dyspnea, hypoxia, interstitial
infiltrates on a radiologic exam, or a decline by more than 5% in
oxygen saturation, and evaluate for etiology. If the pneumonitis is
infectious, patients may be restarted on COPIKTRA at the previous
dose once the infection, pulmonary signs and symptoms resolve. For
moderate non-infectious pneumonitis (Grade 2), treat with systemic
corticosteroids and resume COPIKTRA at a reduced dose upon
resolution. If non-infectious pneumonitis recurs or does not
respond to steroid therapy, discontinue COPIKTRA. For severe or
life-threatening non-infectious pneumonitis, discontinue COPIKTRA
and treat with systemic steroids.
Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation
developed in 8% and 2%, respectively, of patients receiving
COPIKTRA 25 mg BID (N=442). Two percent of patients had both an ALT
or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time
to onset of any grade transaminase elevation was 2 months (range: 3
days to 26 months), with a median event duration of 1 month (range:
1 day to 16 months).
Monitor hepatic function during treatment with COPIKTRA. For
Grade 2 ALT/AST elevation (> 3 to 5 X ULN), maintain COPIKTRA
dose and monitor at least weekly until return to < 3 X ULN. For
Grade 3 ALT/AST elevation (> 5 to 20 X ULN), withhold COPIKTRA
and monitor at least weekly until return to < 3 X ULN. Resume
COPIKTRA at the same dose (first occurrence) or at a reduced dose
for subsequent occurrences. For grade 4 ALT/AST elevation (> 20
X ULN), discontinue COPIKTRA.
Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of
patients receiving COPIKTRA 25 mg BID (N=442), with Grade 4
neutropenia occurring in 24% of all patients. Median time to onset
of grade ≥3 neutropenia was 2 months (range: 3 days to 31 months),
with 75% of cases occurring within 4 months.
Monitor neutrophil counts at least every 2 weeks for the first 2
months of COPIKTRA therapy, and at least weekly in patients with
neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in
patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4).
Monitor until ANC is > 0.5 Gi/L, then resume COPIKTRA at same
dose for the first occurrence or at a reduced dose for subsequent
occurrences.
Embryo-Fetal Toxicity: Based on findings in animals and
its mechanism of action, COPIKTRA can cause fetal harm when
administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Conduct pregnancy testing before
initiating COPIKTRA treatment. Advise females of reproductive
potential and males with female partners of reproductive potential
to use effective contraception during treatment and for at least 1
month after the last dose.
ADVERSE REACTIONS
B-cell Malignancies Summary
Fatal adverse reactions within 30 days of the last dose occurred
in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious
adverse reactions were reported in 289 patients (65%). The most
frequent serious adverse reactions that occurred were infection
(31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and
pneumonitis (5%).
Adverse reactions resulted in treatment discontinuation in 156
patients (35%) most often due to diarrhea or colitis, infection,
and rash. COPIKTRA was dose reduced in 104 patients (24%) due to
adverse reactions, most often due to diarrhea or colitis and
transaminase elevation. The most common adverse reactions (reported
in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash,
fatigue, pyrexia, cough, nausea, upper respiratory infection,
pneumonia, musculoskeletal pain and anemia.
CLL/SLL
Fatal adverse reactions within 30 days of the last dose occurred
in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155)
of patients treated with ofatumumab. Serious adverse reactions were
reported in 73% (115/158) of patients treated with COPIKTRA and
most often involved infection (38%; 60/158) and diarrhea or colitis
(23%; 36/158). COPIKTRA was discontinued in 57 patients (36%), most
often due to diarrhea or colitis, infection, and rash. COPIKTRA was
dose reduced in 46 patients (29%) due to adverse reactions, most
often due to diarrhea or colitis and rash. The most common adverse
reactions with COPIKTRA (reported in ≥20% of patients) were
diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract
infection, pneumonia, rash, fatigue, nausea, anemia and cough.
DRUG INTERACTIONS
- CYP3A Inducers: Coadministration with a strong CYP3A inducer
may reduce COPIKTRA efficacy. Avoid coadministration with strong
CYP3A4 inducers.
- CYP3A Inhibitors: Coadministration with a strong CYP3A
inhibitor may increase the risk of COPIKTRA toxicities. Reduce
COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4
inhibitor.
- CYP3A Substrates: Coadministration of COPIKTRA with sensitive
CYP3A4 substrates may increase the risk of toxicities of these
drugs. Consider reducing the dose of the sensitive CYP3A4 substrate
and monitor for signs of toxicities of the coadministered sensitive
CYP3A substrate.
Please see the full Prescribing Information, including BOXED
WARNING, and patient Medication Guide found on
www.COPIKTRA.com.
About Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic
lymphoma (SLL) are cancers that affect lymphocytes and are
essentially the same disease, with the only difference being the
location where the cancer primarily occurs. When most of the cancer
cells are located in the bloodstream and the bone marrow, the
disease is referred to as CLL, although the lymph nodes and spleen
are often involved. When the cancer cells are located mostly in the
lymph nodes, the disease is called SLL. The symptoms of CLL/SLL
include a tender, swollen abdomen and feeling full even after
eating only a small amount. Other symptoms can include fatigue,
shortness of breath, anemia, bruising easily, night sweats, weight
loss, and frequent infections. However, many patients with CLL/SLL
will live for years without symptoms. There are approximately
200,000 patients in the US affected by CLL/SLL with nearly 20,000
new diagnoses this year alone. While there are therapies currently
available, real-world data reveals that a significant number of
patients either relapse following treatment, become refractory to
current agents, or are unable to tolerate treatment, representing a
significant medical need. The potential of additional oral agents,
particularly as a monotherapy that can be used in the general
community physician’s armamentarium, may hold significant value in
the treatment of patients with CLL/SLL.
About Peripheral T-Cell Lymphoma
Peripheral T-cell lymphoma (PTCL) is a rare, aggressive type of
non-Hodgkin lymphoma (NHL) that develops in mature white blood
cells called “T cells” and “natural killer (NK) cells”5 which
circulate with the lymphatic system.6 PTCL accounts for between
10-15% of all non-Hodgkin lymphomas (NHLs) and generally affects
people aged 60 years and older.1 Although there are many different
subtypes of peripheral T-cell lymphoma, they often present in a
similar way, with widespread, enlarged, painless lymph nodes in the
neck, armpit or groin.6 There is currently no established standard
of care for patients with relapsed or refractory disease.5
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a commercial
biopharmaceutical company committed to the development and
commercialization of medicines to improve the lives of patients
diagnosed with cancer. We are driven by the strength, tenacity and
courage of those battling cancer – single-minded in our resolve to
deliver new therapies that not only keep cancer at bay, but improve
the lives of patients diagnosed with cancer. Because for us, it’s
personal.
Our first FDA approved product is now available for the
treatment of patients with certain types of indolent non-Hodgkin’s
lymphoma (iNHL). Our pipeline comprises product candidates that
seek to treat cancer by modulating the local tumor
microenvironment. For more information, please visit
www.verastem.com.
Forward looking statements notice
This press release and the commentary in the conference call to
be held today each include forward-looking statements about
Verastem Oncology’s strategy, future plans and prospects, including
statements regarding the development and activity of Verastem
Oncology’s lead product COPIKTRA, and Verastem Oncology’s PI3K
program generally, its commercialization of COPIKTRA, the potential
commercial success of COPIKTRA, including financial guidance and
patient population estimates, the anticipated adoption of COPIKTRA
by patients and physicians, the structure of its planned and
pending clinical trials and the timeline and indications for
clinical development, regulatory submissions and commercialization
activities. 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 and
uncertainties, among other things, regarding: the commercial
success of COPIKTRA in the United States; physician and patient
adoption of COPIKTRA, including those related to the safety and
efficacy of COPIKTRA; the uncertainties inherent in research and
development of COPIKTRA, such as negative or unexpected results of
clinical trials; whether and when any applications for COPIKTRA may
be filed with regulatory authorities in any other jurisdictions;
whether and when regulatory authorities in any other jurisdictions
may approve any such other applications that may be filed for
COPIKTRA, which will depend on the assessment by such regulatory
authorities of the benefit-risk profile suggested by the totality
of the efficacy and safety information submitted and, if approved,
whether COPIKTRA will be commercially successful in such
jurisdictions; our ability to obtain, maintain and enforce patent
and other intellectual property protection for COPIKTRA and our
other product candidates; the scope, timing, and outcome of any
legal proceedings; decisions by regulatory authorities regarding
labeling and other matters that could affect the availability or
commercial potential of COPIKTRA; the fact that regulatory
authorities in the U.S. or other jurisdictions, if approved, could
withdraw approval; whether preclinical testing of our product
candidates and preliminary or interim data from clinical trials
will be predictive of the results or success of ongoing or later
clinical trials; that the timing, scope and rate of reimbursement
for our product candidates is uncertain; that third-party payors
(including government agencies) may not reimburse for COPIKTRA;
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
COPIKTRA or our other product candidates will cause unexpected
safety events, experience manufacturing or supply interruptions or
failures, or result in unmanageable safety profiles as compared to
their levels of efficacy; that COPIKTRA will be ineffective at
treating patients with lymphoid malignancies; that we will be
unable to successfully initiate or complete the clinical
development and eventual commercialization of our product
candidates; that the development and commercialization of our
product candidates will take longer or cost more than planned; that
we may not have sufficient cash to fund our contemplated
operations; that we, CSPC Pharmaceutical Group, Yakult Honsha Co.,
Ltd. or Infinity Pharmaceuticals, Inc. will fail to fully perform
under the duvelisib license agreements; that we may be unable to
make additional draws under our debt facility or obtain adequate
financing in the future through product licensing, co-promotional
arrangements, public or private equity, debt financing or
otherwise; that we will not pursue or submit regulatory filings for
our product candidates, including for duvelisib in patients with
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
or indolent non-Hodgkin lymphoma (iNHL) in other jurisdictions; and
that our 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 the Company’s Quarterly Report on Form
10-Q for the quarterly period ended March 31, 2019, as filed with
the Securities and Exchange Commission (SEC) on May 9, 2019, its
Annual Report on Form 10-K for the year ended December 31, 2018 as
filed with the SEC on March 12, 2019 and in any subsequent filings
with the SEC. The forward-looking statements contained in this
press release reflect Verastem Oncology’s views as of the date
hereof, and the Company does not assume and specifically disclaims
any obligation to update any forward-looking statements whether as
a result of new information, future events or otherwise, except as
required by law.
References
1 Winkler D.G., Faia K.L., DiNitto J.P. 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 K 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 M 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, NCT03372057. 5 The
Leukemia & Lymphoma Society. Peripheral T-Cell Lymphoma Facts.
July 2014. 6 Leukemia Foundation.
http://www.leukaemia.org.au/blood-cancers/lymphomas/non-hodgkin-lymphoma-nhl/peripheral-t-cell-lymphoma
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