Verastem Oncology to Present New COPIKTRA™ (Duvelisib) Dose Modification Data from Patients Treated in the Phase 3 DUO Study
May 15, 2019
Abstract Highlights the Effect of Dose Modification on Response to
COPIKTRA in Adult Patients with CLL/SLL After At Least Two Prior
Therapies
Dose Interruptions of a Median 15 days Do Not Significantly Impact
Response or PFS
Data Demonstrate That Dose Modifications Can be Used to Effectively
Manage Adverse Events
BOSTON–(BUSINESS WIRE)–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 a poster highlighting dose modification data
from the Phase 3 DUO study evaluating COPIKTRA (duvelisib) in patients
with relapsed or refractory chronic lymphocytic leukemia/small
lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. The
poster, entitled “Effect of dose modifications on response to duvelisib
in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial,”
will be presented at the American Society of Clinical Oncology (ASCO)
2019 Annual Meeting, taking place May 31 – June 4, 2019, in Chicago.
COPIKTRA, an 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 this same
indication in September 2018.
“Duvelisib is a potent oral dual inhibitor of PI3K-delta and -gamma with
robust activity in patients with CLL/SLL after at least two prior
therapies,” commented Ian Flinn, MD, PhD, Director, Lymphoma/CLL Program
at Sarah Cannon Research Institute and lead investigator of the DUO
study. “These new data demonstrate that dose modifications may be used
to manage treatment-emergent adverse events (TEAEs) while allowing
patients to remain on therapy, and that dosing interruptions of a median
15 days do not appear to negatively impact response to Duvelisib or
progression-free-survival (PFS).”
“Notably, these data also show that when adverse events of special
interest (AESIs) occur, they tend to show up in the first few months of
treatment, then the proportion of patients experiencing AESIs
decreases,” said Robert Forrester, President and Chief Executive Officer
of Verastem Oncology. “We look forward to sharing these data with the
scientific and medical communities at ASCO this year.”
Effect of Dose Modification on Response to COPIKTRA in Patients with
Relapsed or Refractory CLL/SLL in the Phase 3 DUO Study
The randomized, multicenter, open-label, Phase 3 DUO study, compared
COPIKTRA versus ofatumumab in 319 adult patients with CLL (n=312) or SLL
(n=7) after at least one prior therapy. The study randomized patients
with a 1:1 ratio to receive either COPIKTRA 25mg twice daily until
disease progression or unacceptable toxicity, or ofatumumab, an approved
standard of care treatment for use in CLL/SLL, for 7 cycles. This
analysis examined dose modification patterns and their impact on
response to COPIKTRA. Dose interruptions (DI) or dose reductions (DR) to
15mg, 10mg or 5mg twice daily were permitted per study protocol to
manage TEAEs. Responses were assessed per an Independent Review
Committee (IRC).
Among the 158 COPIKTRA-treated patients in the DUO study, the median
duration of exposure was 11.6 months, versus 5.3 months for patients
treated with ofatumumab. The most common cause of DI was diarrhea (23%),
followed by neutropenia (12%) and pneumonia or colitis (11% each). Among
responders (n=118), median time to first response on COPIKTRA was 1.9
months and the estimated median duration of response was 11.1 months.
Median time to first DI was 3.9 months and median duration of DI was 15
days (range 1 to 133 days). Response to COPIKTRA was improved or
maintained in most patients evaluated for response who had at least one
DI for >1 week (84%) or >2 weeks (82%) followed by at least 3 weeks on
COPIKTRA. In a landmark analysis, median PFS was similar in patients
with DI and those without DI for >1 week (17.8 versus 16.3 months) or >2
weeks (17.8 versus 16.3 months) within the first 3 months. The median
time to DR after a complete response or partial response was 5.6 months
(n=25) and median duration was 3.4 months. Median time to onset across
AESIs after starting COPIKTRA ranged from 2.2 to 4.3 months. Median time
to resolution was within 4 weeks across AESIs. Proportions of patients
experiencing AESIs were stable or decreased over time after 3-6 months:
0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%,
and seldom led to discontinuation of COPIKTRA (≤10%). These findings
support the thesis that DI or DR can be useful in effectively managing
TEAEs with COPIKTRA and that DI of >1-2 weeks or more do not appear to
significantly impact response to COPIKTRA or PFS.
A PDF copy of this poster presentation will be available here
following the conclusion of the presentation.
Details for the ASCO 2019 presentation is as follows:
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Title: Effect of dose modifications on response to |
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Lead author: Ian Flinn, Sarah Cannon Research Institute |
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Session: Hematologic Malignancies – Lymphoma and Chronic |
|
Poster Board#: 277 |
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Abstract #: 7523 |
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Location: McCormick Place, Hall A |
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Date and Time: Monday, June 3, 8:00 – 11:00 a.m. CT |
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 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.
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.
Contacts
Verastem Oncology:
John Doyle
Vice President, Investor
Relations & Finance
+1 781-469-1546
[email protected]
Investors:
Joseph
Rayne
Argot Partners
+1 617-340-6075
[email protected]