[January 19, 2018] |
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Investigational Data Presented at ASCO GI Evaluate ABRAXANE® Regimen for Patients with Locally Advanced Pancreatic Cancer
Celgene Corporation (NASDAQ: CELG) today announced primary endpoint
findings and updated results of secondary endpoints from the phase II
international LAPACT trial of ABRAXANE® (paclitaxel
protein-bound particles for injectable suspension) (albumin-bound) plus
gemcitabine in patients with locally advanced pancreatic cancer. The
results were presented today at the 2018 American Society of Clinical
Oncology Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco,
California.
An analysis of patients with newly diagnosed, locally advanced
pancreatic cancer treated with up to 6 cycles of ABRAXANE + gemcitabine
as an investigational induction therapy (n=106) found that patients had
a median time to treatment failure (TTF) of 8.8 months (90% CI:
6.67-9.82), which exceeded the protocol-specified target of 6.6 months
(primary endpoint). Secondary endpoints included evaluation of the
disease control rate (DCR), overall response rate (ORR), progression
free survival (PFS) and overall survival (OS) in patients treated with
an ABRAXANE + gemcitabine induction therapy. The updated analysis found
a 77.6% DCR = 16 wks (DCR = 16 wks: stable disease (SD) = 16 wks =
44.9%, CR = 0%, PR = 32%) and 65.4% DCR = 24 wks (DCR = 24 wks: SD = 24
wks = 32.7%, CR = 0%, PR = 32%). The ORR was 32% (CR=0%, PR=32%), the
median PFS was 10.8 months (9,26-11.63; 90% CI) and 12-month estimated
OS was 72% (64.5% - 78.9%; 90% CI). One or more treatment emergent
adverse event occurred in 99% of patients during induction. The most
common Grade = 3 adverse events (AE) (=10%) were neutropenia (42%),
anemia (11%), and fatigue (10%).
"Pancreatic cancer remains an extremely challenging disease to treat
because it is often diagnosed at the metastatic stage, and even those
diagnosed with locally advanced disease typically have a poor
prognosis," said Dr. Pascal Hammel, Gastroenterologist/Oncologist,
Hôpital Beaujon, Clichy France. "Disease control is key in our patients
with locally advanced disease, as it may lead to opportunities for
additional treatment interventions, including radiotherapy, or even, in
some favorable cases, surgical resection. The results from this study
are encouraging, as it shows that induction therapy has the potential to
help us achieve disease control in these locally advanced patients."
In this prospective, phase II trial conducted in the US, Canada and
Europe, patients with protocol-defined locally advanced, unresectable
pancreatic cancer received an induction regimen of up to 6 cycles of
ABRAXANE + gemcitabine, followed by the investigator's choice (IC) of
either (a) continuation of the ABRAXANE + gemcitabine regimen, (b)
treatment with chemoradiation, or (c) surgery. More than half of
patients (57.5%, n = 61/106) completed the induction phase with ABRAXANE
+ gemcitabine treatment. Forty two percent (45/106) of patients did not
complete induction treatment and the reasons for treatment
discontinuation during induction included adverse events (n = 20),
progressive disease (n = 8), protocol non-compliance (n = 5), physician
decision (n = 6), death (n = 2), and other reasons (n = 4). At the time
of data cut-off, 45 patients in the intent to treat cohort received IC
therapy after induction: 11% (12/106) of patients continued ABRAXANE +
gemcitabine per the protocol; 16% (17/106) received chemoradiation; and
15% of patients (16/106) with unresectable disease at the start of the
study underwent tumor resection surgery following ABRAXANE + gemcitabine
induction therapy. The LAPACT presentation also reported
patient-reported quality of life findings across twenty-nine different
symptom measures using the EORTC QLQ-C30 questionnaires.
Other relevant grade =3 TEAEs included thrombocytopenia (7.5%),
peripheral sensory neuropathy (3.8%), diarrhea (3.8%), and febrile
neutropenia (3.8%). AEs of any grade included: neutropenia (58.5%),
fatigue (50%), anemia (47.2%), diarrhea (46.2%), thrombocytopenia
(41.5%), peripheral sensory neuropathy (23.6%), and febrile neutropenia
(3.8%).
"Since its approval to treat metastatic pancreatic cancer in 2013, the
ABRAXANE + gemcitabine regimen has become a standard of care in
first-line metastatic pancreatic cancer," said Nadim Ahmed, President,
Hematology and Oncology for Celgene. "The findings from LAPACT offer
insight into the potential of ABRAXANE-based treatment for locally
advanced pancreatic cancer patients and it's encouraging to see a nearly
9-month time to treatment failure in these patients treated with an
ABRAXANE regimen."
ABRAXANE is not indicated for the first-line treatment of locally
advanced pancreatic cancer.
ABOUT LAPACT,
LAPACT is an international, non-randomized, open-label, multi-center,
phase II clinical trial conducted at 42 centers in 5 countries. The
study evaluated the safety and efficacy of the investigational use of
ABRAXANE in combination with gemcitabine as a first-line treatment of
patients with locally advanced pancreatic cancer who were not eligible
for resection surgery at trial initiation.
The trial evaluated 106 patients with locally advanced pancreatic cancer
who had not received prior treatment for their pancreatic cancer and
were classified as unresectable at the start of the trial. Patients were
given ABRAXANE 125 mg/m2 followed by gemcitabine 1000 mg/m2
on days 1, 8 and 15 of a 28-day cycle for up to six cycles. Patients
completing six cycles of treatment were given subsequent
investigator-determined treatment of either: continuation of the
ABRAXANE + gemcitabine regimen; chemoradiation therapy with capecitabine
or gemcitabine + radiation; or surgical intervention. The median age of
the patients was 65 years.
Currently, there are more than 130 studies evaluating the use of
ABRAXANE in patients with pancreatic cancer in combination with more
than 50 novel agents.
ABOUT ABRAXANE
ABRAXANE is indicated for the first-line treatment of patients with
metastatic adenocarcinoma of the pancreas, in combination with
gemcitabine.
Important Safety Information
WARNING - NEUTROPENIA
-
Do not administer ABRAXANE therapy to patients who have baseline
neutrophil counts of less than 1500 cells/mm3.
In order to monitor the occurrence of bone marrow suppression,
primarily neutropenia, which may be severe and result in infection, it
is recommended that frequent peripheral blood cell counts be performed
on all patients receiving ABRAXANE
-
Note: An albumin form of paclitaxel may substantially affect a
drug's functional properties relative to those of drug in solution. DO
NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS
Neutrophil Count
-
ABRAXANE should not be used in patients who have baseline neutrophil
counts of <1500 cells/mm3
Hypersensitivity
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS
Hematologic Effects
-
Bone marrow suppression (primarily neutropenia) is dose-dependent and
a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4
neutropenia occurred in 47% of patients with non-small cell lung
cancer (NSCLC) and 38% of patients with pancreatic cancer
-
Monitor for myelotoxicity by performing complete blood cell counts
frequently, including prior to dosing on Days 1, 8, and 15 for NSCLC
and for pancreatic cancer
-
Do not administer ABRAXANE to patients with baseline absolute
neutrophil counts (ANC) of less than 1500 cells/mm3
-
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and
gemcitabine if the ANC is less than 500 cells/mm3 or
platelets are less than 50,000 cells/mm3 and delay
initiation of the next cycle if the ANC is less than 1500 cells/mm3
or platelet count is less than 100,000 cells/mm3 on Day 1
of the cycle. Resume treatment with appropriate dose reduction if
recommended
Nervous System
-
Sensory neuropathy is dose- and schedule-dependent
-
The occurrence of Grade 1 or 2 sensory neuropathy does not generally
require dose modification
-
If = Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment
until resolution to = Grade 1 for NSCLC and pancreatic cancer followed
by a dose reduction for all subsequent courses of ABRAXANE
Sepsis
-
Sepsis occurred in 5% of patients with or without neutropenia who
received ABRAXANE in combination with gemcitabine
-
Biliary obstruction or presence of biliary stent were risk factors for
severe or fatal sepsis
-
If a patient becomes febrile (regardless of ANC), initiate treatment
with broad-spectrum antibiotics
-
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until
fever resolves and ANC =1500 cells/mm3, then resume
treatment at reduced dose levels
Pneumonitis
-
Pneumonitis, including some cases that were fatal, occurred in 4% of
patients receiving ABRAXANE in combination with gemcitabine
-
Monitor patients for signs and symptoms and interrupt ABRAXANE and
gemcitabine during evaluation of suspected pneumonitis
-
Permanently discontinue treatment with ABRAXANE and gemcitabine upon
making a diagnosis of pneumonitis
Hypersensitivity
-
Severe and sometimes fatal hypersensitivity reactions, including
anaphylactic reactions, have been reported
-
Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be rechallenged with this drug
Hepatic Impairment
-
Because the exposure and toxicity of paclitaxel can be increased with
hepatic impairment, administration of ABRAXANE in patients with
hepatic impairment should be performed with caution
-
Patients with hepatic impairment may be at an increased risk of
toxicity, particularly from myelosuppression, and should be monitored
for development of profound myelosuppression
-
For pancreatic adenocarcinoma, ABRAXANE is not recommended for
patients with moderate to severe hepatic impairment (total bilirubin
>1.5 x ULN and AST =10 x ULN)
Albumin (Human)
-
ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D
-
ABRAXANE can cause fetal harm when administered to a pregnant woman
-
If this drug is used during pregnancy, or if the patient becomes
pregnant while receiving this drug, the patient should be apprised of
the potential hazard to the fetus
-
Women of childbearing potential should be advised to avoid becoming
pregnant while receiving ABRAXANE
Use in Men
-
Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS
-
Among the most common (=20%) adverse reactions in the phase III study,
those with a =5% higher incidence in the ABRAXANE/gemcitabine group
compared with the gemcitabine group are neutropenia (73%, 58%),
fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%,
48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%,
24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite
(36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
-
Of these most common adverse reactions, those with a =2% higher
incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group
compared with the gemcitabine group, respectively, are neutropenia
(38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea
(6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%),
decreased appetite (5%, 2%), and dehydration (7%, 2%)
-
Thrombocytopenia (all grades) was reported in 74% of patients in the
ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
-
The most common serious adverse reactions of ABRAXANE (with a =1%
higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%),
and vomiting (4%)
-
The most common adverse reactions resulting in permanent
discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue
(4%), and thrombocytopenia (2%)
-
The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
-
The most common adverse reactions leading to withholding or delay in
ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue
(8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
-
Other selected adverse reactions with a =5% higher incidence for
all-grade toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group, respectively, are asthenia (19%, 13%), mucositis
(10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%,
7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection
(11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia
(10%, 4%), and depression (12%, 6%)
-
Other selected adverse reactions with a =2% higher incidence for Grade
3-4 toxicity in the ABRAXANE/gemcitabine group compared to the
gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%),
and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel
Formulations
-
Severe and sometimes fatal hypersensitivity reactions have been
reported with ABRAXANE. The use of ABRAXANE in patients previously
exhibiting hypersensitivity to paclitaxel injection or human albumin
has not been studied
-
There have been reports of congestive heart failure, left ventricular
dysfunction, and atrioventricular block with ABRAXANE, primarily among
individuals with underlying cardiac history or prior exposure to
cardiotoxic drugs
-
There have been reports of extravasation of ABRAXANE. Given the
possibility of extravasation, it is advisable to monitor closely the
ABRAXANE infusion site for possible infiltration during drug
administration
DRUG INTERACTIONS
-
Caution should be exercised when administering ABRAXANE concomitantly
with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS
Nursing Mothers
-
It is not known whether paclitaxel is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants, a decision should be
made to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother
Pediatric
-
The safety and effectiveness of ABRAXANE in pediatric patients have
not been evaluated
Geriatric
-
Myelosuppression, peripheral neuropathy, and arthralgia were more
frequent in patients =65 years of age treated with ABRAXANE and
carboplatin in NSCLC
-
Diarrhea, decreased appetite, dehydration, and epistaxis were more
frequent in patients 65 years or older compared with patients younger
than 65 years old who received ABRAXANE and gemcitabine in
adenocarcinoma of the pancreas
Renal Impairment
-
There are insufficient data to permit dosage recommendations in
patients with severe renal impairment or end stage renal disease
(estimated creatinine clearance <30 mL/min)
DOSAGE AND ADMINISTRATION
-
Do not administer ABRAXANE to any patient with total bilirubin greater
than 5 x ULN or AST greater than 10 x ULN
-
Do not administer ABRAXANE to patients with metastatic adenocarcinoma
of the pancreas who have moderate to severe hepatic impairment
-
Dose reductions or discontinuation may be needed based on severe
hematologic, neurologic, cutaneous, or gastrointestinal toxicity
-
Monitor patients closely
Please see full
Prescribing Information, including Boxed WARNING.
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an
integrated global biopharmaceutical company engaged primarily in the
discovery, development and commercialization of innovative therapies for
the treatment of cancer and inflammatory diseases through
next-generation solutions in protein homeostasis, immuno-oncology,
epigenetics, immunology and neuro-inflammation. For more information,
please visit www.celgene.com.
Follow Celgene on Social Media: @Celgene,
Pinterest,
LinkedIn,
FaceBook
and YouTube.
Forward-Looking Statements
This press release contains forward-looking statements, which are
generally statements that are not historical facts. Forward-looking
statements can be identified by the words "expects," "anticipates,"
"believes," "intends," "estimates," "plans," "will," "outlook" and
similar expressions. Forward-looking statements are based on
management's current plans, estimates, assumptions and projections, and
speak only as of the date they are made. We undertake no obligation to
update any forward-looking statement in light of new information or
future events, except as otherwise required by law. Forward-looking
statements involve inherent risks and uncertainties, most of which are
difficult to predict and are generally beyond our control. Actual
results or outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, many of which are discussed in more detail in our Annual Report
on Form 10-K and our other reports filed with the Securities and
Exchange Commission.
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