Multiple analyses examined ABRAXANE (paclitaxel
protein-bound particles for injectable suspension)(albumin-bound)
and gemcitabine followed by 5-FU-based regimens
Celgene Corporation (NASDAQ: CELG) today announced that results
from multiple analyses presented during the 2016 ASCO
Gastrointestinal Cancers Symposium (ASCO GI) evaluated the outcomes
of second-line treatments following ABRAXANE® (paclitaxel
protein-bound particles for injectable suspension)(albumin-bound)
and gemcitabine (AG) in first-line metastatic pancreatic cancer
patients.
In particular, a post-hoc analysis of MPACT, the pivotal phase
III study of AG compared with gemcitabine alone in first-line
metastatic pancreatic cancer evaluated the outcomes of patients who
received a second-line treatment during an observational extension
of the study.
A total of 347 (40%) patients received second-line therapy in
the extension, and of those patients, the majority (77%, including
132 who had received AG in the first line and 135 who had received
gemcitabine alone) received 5-FU-based therapies or capecitabine
combinations.
A post hoc analysis of overall survival (OS) was conducted and
demonstrated that patients (n=170) who received AG, followed by
second-line therapy had a median OS of 12.8 months, compared with
9.9 months for patients (n= 177) who received gemcitabine alone,
followed by second-line therapy. Of patients receiving second-line
therapies, the majority (n=132) received 5FU or
capecitabine-containing regimens and had a median OS of 13.5
months. Patients receiving FOLFIRINOX (FFX) following AG (n=18) had
the longest median overall survival at 15.7 months. OS was
calculated using the Kaplan-Meier method.
The analysis provided data demonstrating the feasibility of
second-line treatment in patients with MPC after first-line AG.
“As the body of research and approved options increase in
pancreatic cancer, there is now evidence that second-line treatment
is feasible and beneficial for certain patients with metastatic
disease,” said Dr. David Goldstein, medical oncologist at Prince of
Wales Hospital in Sydney, Australia and the lead investigator of
the analysis. “We are seeing an exciting evolution in the treatment
of this disease and for patients and physicians, it is now time to
consider a total treatment plan when choosing an initial
therapy.”
A retrospective cohort study performed using data U.S. community
data from Navigating Cancer, an electronic medical record platform,
sought to compare the time to treatment discontinuation and
database persistence, used as a proxy for OS, between AG and FFX in
the first-line setting.
The analysis showed that time to treatment discontinuation and
database persistence for patients with first-line metastatic
pancreatic cancer (n=202) were numerically similar (8.6 in each
arm) between AG (n=122) and FFX (n=80). With the exception of the
age of patients, which favored FFX (median age 67 for AG years vs.
61.4 years for FFX), baseline characteristics were generally
similar between the groups.
There was a higher incidence of adverse events (all grades) with
FFX compared with AG (95% vs. 84%). Most common AE’s that led to
discontinuation were anemia (8% for FFX and 2% for AG), neutropenia
(6% for each), and dehydration (5% and 3%, respectively)
The analysis also evaluated various treatment plans including
first-line AG, followed by second-line 5-FU-based therapies and
first-line FFX, followed by second-line gemcitabine-based
therapies. The duration of treatment for the AG arm was a median
8.7 months, compared with 8.4 months for the FFX arm (p=0.52).
Further, the database persistence (proxy for OS) for patients
receiving AG followed by 5-FU-based therapies (n=25) was a median
12.7 months, compared with 9.3 months for patients receiving FFX
followed by gemcitabine-based therapies (n=41) (p=0.48).
There were four additional studies evaluating the sequence of AG
followed by 5-FU-based therapies at the meeting:
- Outcome of second-line treatment (2L
Tx) following nab-paclitaxel (nab-P) + gemcitabine (G) or G alone
for metastatic pancreatic cancer (MPC). (Goldstein #333)
- Comparative effectiveness and resource
utilization of nab-paclitaxel plus gemcitabine (nab-P+G) versus
FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic
adenocarcinoma (PDAC) in a U.S. community oncology setting (Braiteh
#433)
- Can the sequence of chemotherapy
regimens influence outcome in patients with metastatic pancreatic
adenocarcinoma (MPAC)? (Schmidt #428)
- Irinotecan and infusional
5-fluorouracil (mFOLFIRI) in patients with refractory advanced
pancreas cancer (APC): A single institution experience. (Bupathi
#215)
Indications
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
CONTRAINDICATIONSNeutrophil Counts
- 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 PRECAUTIONSHematologic Effects
- Bone marrow suppression (primarily
neutropenia) is dose-dependent and a dose-limiting toxicity of
ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in
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 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 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 POPULATIONSNursing 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
- 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 patients
with metastatic adenocarcinoma of the pancreas who have moderate to
severe hepatic impairment
- Do not administer ABRAXANE to any
patient with total bilirubin greater than 5 x ULN or AST greater
than 10 x ULN
- 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.
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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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