|[June 01, 2014]
ARIAD Announces Initial Data from Phase 2 Trial of Ponatinib in Patients with Gastrointestinal Stromal Tumors
CAMBRIDGE, Mass. & CHICAGO --(Business Wire)--
Pharmaceuticals, Inc. (NASDAQ:ARIA) today announced, for the first
time, data from its Phase 2 trial of Iclusig® (ponatinib)
in adult patients with refractory metastatic and/or unresectable
gastrointestinal stromal tumors (GIST). The initial data show that
ponatinib has anti-tumor activity in patients with advanced GIST,
particularly in patients with KIT exon 11 mutations, after failure of at
least one prior tyrosine kinase inhibitor (TKI). The primary endpoint
for the trial, clinical benefit rate (CBR) at 16 weeks for patients with
KIT exon 11 mutations, was 50 percent, with a median follow-up of six
These data are being featured today in an oral presentation at 10:00
a.m. CT at the Annual Meeting of the American Society of Clinical
Oncology (ASCO) being held in Chicago.
The Phase 2 trial of ponatinib in GIST enrolled 35 patients as of April
7, 2014. The trial is ongoing, and the FDA partial clinical hold to new
patient enrollment has been lifted. The patient population in the trial
is heavily pre-treated, with 46 percent having failed three prior
GIST-approved TKIs. Patients were enrolled into two cohorts based on the
presence (Cohort A) or absence (Cohort B) of KIT exon 11 mutations.
Primary KIT mutations occur in approximately 85 percent of patients with
GIST. The most common mutation is on exon 11 (~70 percent).
Preclinically, ponatinib showed compelling activity against activating
exon 11 mutations.
"These initial data support the preclinical findings that ponatinib has
activity against the acquired mutations in KIT which patients with GIST
can develop following treatment with other targeted TKIs," stated
Michael C. Heinrich, M.D., professor of medicine and cell/developmental
biology at the Knight Cancer Institute, Oregon Health & Science
University, Portland, Oregon. "Treatment with approved agents in the
second or third-line settings is associated with a median time to
progression of less than six months for each line of treatment. There is
a great unmet need for additional treatments for this population of
patients. Stable disease at 16 weeks is an important milestone for
refractory patients so I believe these early clinical responses to
ponatinib are encouraging."
The Phase 2 trial is an open-label, multicenter trial designed to
evaluate the efficacy and safety of ponatinib in patients with
metastatic and/or unresectable GIST after prior failure of approved TKI
therapies. The trial is being conducted at three sites in the United
States: Dana Farber Cancer Institute, Fox Chase Cancer Center and Oregon
Health Science University.
Patients in the trial received the same starting dose of ponatinib - 45
mg administered orally once daily - as used in patients with
Philadelphia chromosome-positive (Ph+) leukemias. Dose reductions to
manage drug-related adverse events were allowed with re-escalation once
The CBR, measuring disease control and defined as the composite of
complete response, partial response, and stable disease lasting 16 weeks
or more, is the primary endpoint for the trial and was analyzed in
Cohort A. Secondary endpoints include progression-free survival (PFS),
objective response rate (ORR), overall survival (OS), safety and
pharmacokinetic parameters, and CBR in Cohort B.
"We are pleased with these initial findings of ponatinib's activity in
patients with refractory GIST," stated Frank G. Haluska, M.D., Ph.D.,
senior vice president and chief medical officer at ARIAD. "These data
demonstrate clinical proof of concept for ponatinib in GIST and form the
basis for planning registrational studies of ponatinib in patients with
Anti-tumor Activity in Refractory GIST Patients
The CBR in GIST patients with KIT exon 11 mutations was 50% (11 of 22
patients). The overall CBR was 42% (14 of 33 patients).
With a median follow-up of 6 months, 40% of patients (14 of 35
patients) remain on ponatinib treatment and have received ponatinib
for at least 6 months.
The median time since diagnosis of GIST was 6 years, with 46% of the
patients enrolled in the study having been treated with 3 prior TKIs.
Patients on study received a dose of 45 mg per day. The dose was
reduced in 12 patients (34%), and 13 patients (37%) had dose
interruptions of 3 or more days.
Of 33 patients (excluding 2 patients who were discontinued at FDA's
request), 14 patients (42%) had CBR: 11 of 22 (50%) in Cohort A, the
primary endpoint for this study, and 3 of 11 (27%) in Cohort B. The
ORR in Cohorts A and B were 9% and 0%, respectively.
Median PFS for patients in Cohort A, Cohort B and all patients are 7,
4 and 7 months, respectively.
Safety in Refractory GIST Patients
The safety profile of ponatinib in refractory GIST patients is
consistent with observations in the Phase 1 and pivotal Phase 2 PACE
studies of ponatinib in Ph+ leukemias, except that the incidence of
myelosuppression in GIST is lower than that seen in the leukemia
trials. The most common treatment-related adverse events in this trial
were rash (57%), fatigue (49%), myalgia (46%), dry skin (43%),
headache (43%), and constipation (40%) with the majority of these
being grades 1 or 2 in severity.
The most common serious adverse events were abdominal pain (11%),
fatigue (6%), nausea (6%) and vomiting (6%). There was one vascular
occlusive event of myocardial ischemia (3%) and one case of right
ventricular dysfunction (3%). There was one death in the trial in a
patient with pneumonia.
For more information about this trial, patients and physicians should
call the U.S. toll-free number 1-877-621-2302 or the international
number 1-617-621-2302, or e-mail inquiries to Clinicaltrials@ariad.com.
Investor and Analyst Briefing and Webcast
ARIAD will host an investor and analyst briefing from ASCO on Monday
June 2, 2014. This breakfast meeting will feature Dr. Lyudmila Bazhenova
from UC San Diego Moores Cancer Center to discuss the AP26113 clinical
data being presented at ASCO, Dr. Michael J. Mauro from Memorial Sloan
Kettering Cancer Center to discuss clinical data on ponatinib in CML,
and Dr. Michael C. Heinrich from Oregon Health & Science University to
discuss ponatinib clinical data in GIST.
The meeting will be webcast live along with slides and can be accessed
by visiting the investor relations section of the Company's website at http://investor.ariad.com.
Monday, June 2, 2014
7:30 a.m. to 8:30 a.m. (CT)
Hilton Chicago, Marquette Room
A replay of the investor event will be available on the ARIAD website
approximately three hours after the presentation and will be archived on
the site for four weeks. To ensure a timely connection to the live
webcast, participants should log onto the webcast at least 15 minutes
prior to the scheduled start time.
According to the American Cancer Society, approximately 4,000 to 5,000
people develop gastrointestinal stromal tumors (GIST) each year in the
United States. Approved agents for the treatment of patients with GIST
include imatinib for newly diagnosed patients, sunitinib for patients in
whom imatinib has failed, and regorafenib for patients who have failed
imatinib and sunitinib. Patients can develop resistance to any of these
therapies by acquiring secondary KIT mutations.
About Iclusig® (ponatinib)
Iclusig is approved in the U.S., EU and Switzerland. Iclusig is a kinase
inhibitor indicated in the U.S. for the:
Treatment of adult patients with T315I-positive chronic myeloid
leukemia (chronic phase, accelerated phase, or blast phase) or
T315I-positive Philadelphia chromosome positive acute lymphoblastic
leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or
blast phase chronic myeloid leukemia or Ph+ ALL for whom no other
tyrosine kinase inhibitor (TKI) therapy is indicated.
IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING
WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning
Vascular Occlusion: Arterial and venous thrombosis and occlusions
have occurred in at least 27% of Iclusig treated patients, including
fatal myocardial infarction, stroke, stenosis of large arterial
vessels of the brain, severe peripheral vascular disease, and the need
for urgent revascularization procedures. Patients with and without
cardiovascular risk factors, including patients less than 50 years
old, experienced these events. Monitor for evidence of thromboembolism
and vascular occlusion. Interrupt or stop Iclusig immediately for
vascular occlusion. A benefit risk consideration should guide a
decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of
Iclusig-treated patients. Monitor cardiac function. Interrupt or stop
Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in
Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig
if hepatotoxicity is suspected.
Vascular Occlusion: Arterial and venous thrombosis and
occlusions, including fatal myocardial infarction, stroke, stenosis of
large arterial vessels of the brain, severe peripheral vascular disease,
and the need for urgent revascularization procedures have occurred in at
least 27% of Iclusig-treated patients from the phase 1 and phase 2
trials. Iclusig can also cause recurrent or multi-site vascular
occlusion. Overall, 20% of Iclusig-treated patients experienced an
arterial occlusion and thrombosis event of any grade. Fatal and
life-threatening vascular occlusion has occurred within 2 weeks of
starting Iclusig treatment and in patients treated with average daily
dose intensities as low as 15 mg per day. The median time to onset of
the first vascular occlusion event was 5 months. Patients with and
without cardiovascular risk factors have experienced vascular occlusion
although these events were more frequent with increasing age and in
patients with prior history of ischemia, hypertension, diabetes, or
hyperlipidemia. Interrupt or stop Iclusig immediately in patients who
develop vascular occlusion events.
Heart Failure: Fatal and serious heart failure or left
ventricular dysfunction occurred in 5% of Iclusig-treated patients
(22/449). Eight percent of patients (35/449) experienced any grade of
heart failure or left ventricular dysfunction. Monitor patients for
signs or symptoms consistent with heart failure and treat as clinically
indicated, including interruption of Iclusig. Consider discontinuation
of Iclusig in patients who develop serious heart failure.
Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver
failure and death. Fulminant hepatic failure leading to death occurred
in an Iclusig-treated patient within one week of starting Iclusig. Two
additional fatal cases of acute liver failure also occurred. The fatal
cases occurred in patients with blast phase CML (BP-CML) or Philadelphia
chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe
hepatotoxicity occurred in all disease cohorts. Iclusig treatment may
result in elevation in ALT, AST, or both. Monitor liver function tests
at baseline, then at least monthly or as clinically indicated.
Interrupt, reduce or discontinue Iclusig as clinically indicated.
Hypertension: Treatment-emergent hypertension (defined as
systolic BP=140 mm Hg or diastolic BP=90 mm Hg on at least one occasion)
occurred in 67% of patients (300/449). Eight patients treated with
Iclusig (2%) experienced treatment-emergent symptomatic hypertension as
a serious adverse reaction, including one patient (<1%) with
hypertensive crisis. Patients may require urgent clinical intervention
for hypertension associated with confusion, headache, chest pain, or
shortness of breath. In 131 patients with Stage 1 hypertension at
baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and
manage blood pressure elevations during Iclusig use and treat
hypertension to normalize blood pressure. Interrupt, dose reduce, or
stop Iclusig if hypertension is not medically controlled.
Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of
patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in
discontinuation or treatment interruption in 6% of patients (25/449).
The incidence of treatment-emergent lipase elevation was 41%. Check
serum lipase every 2 weeks for the first 2 months and then monthly
thereafter or as clinically indicated. Consider additional serum lipase
monitoring in patients with a history of pancreatitis or alcohol abuse.
Dose interruption or reduction may be required. In cases where lipase
elevations are accompanied by abdominal symptoms, interrupt treatment
with Iclusig and evaluate patients for pancreatitis. Do not consider
restarting Iclusig until patients have complete resolution of symptoms
and lipase levels are less than 1.5 x ULN.
Neuropathy: Peripheral and cranial neuropathy have occurred in
Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated
patients experienced a peripheral neuropathy event of any grade (2%,
grade 3/4). In clinical trials, the most common peripheral neuropathies
reported were peripheral neuropathy (4%, 18/449), paresthesia (4%,
17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449).
Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients
(<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65)
developed neuropathy during the first month of treatment. Monitor
patients for symptoms of neuropathy, such as hypoesthesia,
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic
pain or weakness. Consider interrupting Iclusig and evaluate if
neuropathy is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness
or blurred vision have occurred in Iclusig-treated patients. Retinal
toxicities including macular edema, retinal vein occlusion, and retinal
hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or
corneal irritation, dry eye, or eye pain occurred in 13% of patients.
Visual blurring occurred in 6% of the patients. Other ocular toxicities
include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative
keratitis. Conduct comprehensive eye exams at baseline and periodically
Hemorrhage: Serious bleeding events, including fatalities,
occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic
events occurred in 24% of patients. The incidence of serious bleeding
events was higher in patients with accelerated phase CML (AP-CML),
BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all, occurred in
patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or
severe hemorrhage and evaluate.
Fluid Retention: Serious fluid retention events occurred in 3%
(13/449) of patients treated with Iclusig. One instance of brain edema
was fatal. In total, fluid retention occurred in 23% of the patients.
The most common fluid retention events were peripheral edema (16%),
pleural effusion (7%), and pericardial effusion (3%). Monitor patients
for fluid retention and manage patients as clinically indicated.
Interrupt, reduce, or discontinue Iclusig as clinically indicated.
Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a
requirement for pacemaker implantation occurred in 1% (3/449) of
Iclusig-treated patients. Advise patients to report signs and symptoms
suggestive of slow heart rate (fainting, dizziness, or chest pain).
Supraventricular tachyarrhythmias occurred in 5% (25/449) of
Iclusig-treated patients. Atrial fibrillation was the most common
supraventricular tachyarrhythmia and occurred in 20 patients. For 13
patients, the event led to hospitalization. Advise patients to report
signs and symptoms of rapid heart rate (palpitations, dizziness).
Interrupt Iclusig and evaluate.
Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred
in 48% (215/449) of patients treated with Iclusig. The incidence of
these events was greater in patients with AP-CML, BP-CML and Ph+ ALL
than in patients with CP-CML. Obtain complete blood counts every 2 weeks
for the first 3 months and then monthly or as clinically indicated, and
adjust the dose as recommended.
Tumor Lysis Syndrome: Two patients (<1%) with advanced disease
(AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious
tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients
overall; the majority had CP-CML (19 patients). Due to the potential for
tumor lysis syndrome in patients with advanced disease, ensure adequate
hydration and treat high uric acid levels prior to initiating therapy
Compromised Wound Healing and Gastrointestinal Perforation: Since
Iclusig may compromise wound healing, interrupt Iclusig for at least 1
week prior to major surgery. Serious gastrointestinal perforation
(fistula) occurred in one patient 38 days post-cholecystectomy.
Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig
is used during pregnancy, or if the patient becomes pregnant while
taking Iclusig, the patient should be apprised of the potential hazard
to the fetus. Advise women to avoid pregnancy while taking Iclusig.
Most common non-hematologic adverse reactions: (=20%) were
hypertension, rash, abdominal pain, fatigue, headache, dry skin,
constipation, arthralgia, nausea, and pyrexia. Hematologic adverse
reactions included thrombocytopenia, anemia, neutropenia, lymphopenia,
Please see the full U.S. Prescribing
Information for Iclusig, including the Boxed Warning, for
additional important safety information.
ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts
and Lausanne, Switzerland, is an integrated global oncology company
focused on transforming the lives of cancer patients with breakthrough
medicines. ARIAD is working on new medicines to advance the treatment of
various forms of chronic and acute leukemia, lung cancer and other
difficult-to-treat cancers. ARIAD utilizes computational and structural
approaches to design small-molecule drugs that overcome resistance to
existing cancer medicines. For additional information, visit http://www.ariad.com
or follow ARIAD on Twitter (News - Alert) (@ARIADPharm).
This press release contains "forward-looking statements" including, but
not limited to, statements relating to initial clinical data on
ponatinib in refractory patients with gastrointestinal stromal tumors
and its potential for future registrational studies. Forward-looking
statements are based on management's expectations and are subject to
certain factors, risks and uncertainties that may cause actual results,
outcome of events, timing and performance to differ materially from
those expressed or implied by such statements. These risks and
uncertainties include, but are not limited to, preclinical data and
early-stage clinical data that may not be replicated in later-stage
clinical studies, the costs associated with our research, development,
manufacturing and other activities, the conduct, timing and results of
pre-clinical and clinical studies of our product candidates, the
adequacy of our capital resources and the availability of additional
funding, and other factors detailed in the Company's public filings with
the U.S. Securities and Exchange Commission. The information contained
in this press release is believed to be current as of the date of
original issue. The Company does not intend to update any of the
forward-looking statements after the date of this document to conform
these statements to actual results or to changes in the Company's
expectations, except as required by law.
Iclusig® is a registered trademark of ARIAD Pharmaceuticals,
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