Phase II LAPACT trial results reported on the
safety and efficacy of ABRAXANE + gemcitabine induction therapy on
tumor burden, disease control, and symptoms
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 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 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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