Approval includes the first powder for oral
suspension formulation of a tyrosine kinase inhibitor developed for
administration in pediatric patients
Bristol-Myers Squibb Company (NYSE:BMY) today announced that the
European Commission (EC) has expanded the indication for Sprycel
(dasatinib) to include the treatment of children and adolescents
aged 1 year to 18 years with Philadelphia chromosome-positive (Ph+)
chronic myeloid leukemia (CML) in chronic phase (CP), and to
include a powder for oral suspension formulation. The approval
follows a positive opinion issued by the European Medicines
Agency's Committee for Medicinal Products for Human Use on April
26, 2018, and makes Sprycel the first ever tyrosine kinase
inhibitor to be approved in a powder formulation for administration
in pediatric patients and patients who cannot swallow tablets.
The EC approval is based on data from CA180-226 (NCT00777036),
the largest prospective trial evaluating the safety and efficacy of
Sprycel in pediatric patients newly diagnosed with CP-CML, and in
those resistant to or intolerant of imatinib.
“Treatment options for pediatric patients with CML are limited,
as are formulations that correspond with the unique demands of
children with cancer,” said Fouad Namouni, M.D., head of
development, Oncology, Bristol-Myers Squibb. “Our decision to
pursue an expanded indication for Sprycel in this new patient
population and as a new formulation is indicative of our commitment
to extending the potential of our medicines to address the unmet
needs of patients with cancer, regardless of the incidence of the
disease.”
In the Phase 2 CA180-226 trial, at minimum two-year follow-up,
patients with CP-CML resistant to or intolerant of imatinib who
received Sprycel demonstrated a cumulative major cytogenetic
response (MCyR) rate of 55.2% (95% CI: 36, 74) 3 months into
treatment, exceeding the defined threshold of clinical interest
(>30%) for the primary endpoint of the cohort and increasing
over time to greater than 90% (95% CI: 73, 98) at 24 months. Newly
diagnosed patients with CP-CML who received Sprycel as a tablet or
as powder for oral suspension achieved a cumulative complete
cytogenetic response (CCyR) rate, the primary endpoint in the
cohort, of 64% (95% CI: 53, 74) as early as 6 months into
treatment, exceeding the defined threshold of clinical interest
(>55%) and increasing over time to 94% (95% CI: 87, 98) at 24
months. The secondary endpoint of estimated progression-free
survival at 48 months was greater than 75% for patients resistant
to or intolerant of imatinib and greater than 90% for patients who
received Sprycel as a first-line therapy.
Sprycel was shown to have a comparable safety profile in
pediatric patients with CP-CML to that reported in adults with
CP-CML. The most commonly reported adverse events in newly
diagnosed patients treated with Sprycel were nausea/vomiting (20%),
rash (19%) and diarrhea (18%), and in imatinib-intolerant or
-resistant patients were nausea/vomiting (31%), myalgia/arthralgia
(17%), fatigue (14%) and rash (14%). In this study, there were no
reported events of pleural/pericardial effusion, pulmonary
edema/hypertension or pulmonary arterial hypertension related to
Sprycel. Study results were published in the Journal of Clinical
Oncology in March 2018.
The recommended starting dosage for Sprycel in
pediatric patients with Ph+ CP-CML is based on body weight. The
Sprycel powder for oral suspension (PFOS) is for patients weighing
10 kg or less, or who cannot swallow tablets whole. The recommended
dose for both the tablet and PFOS formulations should be
recalculated every three months based on changes in body weight, or
more often if necessary. Sprycel tablets should be swallowed
whole and should not be crushed, cut or chewed. The exposure in
patients receiving a crushed tablet is lower than in those
swallowing an intact tablet. The Sprycel tablet and PFOS
formulations are not bioequivalent. Patients should only switch
between the tablet and PFOS formulations at the discretion of a
medical professional, who will decide the right formulation and
dose based on the patient’s weight.
About Chronic Myeloid
Leukemia
Chronic myeloid leukemia is a type of leukemia in which the body
produces an uncontrolled number of abnormal white blood cells.1
Chronic myeloid leukemia occurs when pieces of two different
chromosomes (chromosomes 9 and 22) break off and attach to each
other.2 The newly formed chromosome is called the Philadelphia
chromosome, which contains an abnormal gene called the BCR-ABL
gene. This gene produces the BCR-ABL protein that signals cells to
make too many white blood cells.2 There is no known cause for the
genetic change that results in CML.3
About Sprycel
Sprycel first received FDA approval in 2006 for the treatment of
adults with Philadelphia chromosome-positive (Ph+) chronic myeloid
leukemia (CML) in chronic phase (CP) who are resistant or
intolerant to prior therapy including imatinib. At that time,
Sprycel also received FDA approval for adults with Ph+ acute
lymphoblastic leukemia (ALL) who are resistant or intolerant to
prior therapy. Sprycel is approved and marketed for these
indications in more than 60 countries.
Sprycel is also an FDA-approved treatment for adults with newly
diagnosed Ph+ CML-CP, and in November 2017, Sprycel received FDA
approval for the expanded indication for treatment in pediatric
patients with Ph+ CML-CP. The adult indication is approved in more
than 50 countries.
U.S. FDA-APPROVED INDICATIONS FOR
SPRYCEL®
SPRYCEL® (dasatinib) is indicated for the treatment of
adults with:
- Newly diagnosed Philadelphia
chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic
phase
- Chronic, accelerated, or myeloid or
lymphoid blast phase Ph+ CML with resistance or intolerance to
prior therapy including imatinib
- Philadelphia chromosome-positive acute
lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to
prior therapy
SPRYCEL (dasatinib) is indicated for the treatment of pediatric
patients with:
IMPORTANT SAFETY
INFORMATION
Myelosuppression
Treatment with SPRYCEL is associated with severe (NCI CTCAE
Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur
earlier and more frequently in patients with advanced phase CML or
Ph+ ALL than in patients with chronic phase CML. Myelosuppression
was reported in patients with normal baseline laboratory values as
well as in patients with pre-existing laboratory abnormalities.
- In patients with chronic phase CML,
perform complete blood counts (CBCs) every 2 weeks for 12 weeks,
then every 3 months thereafter, or as clinically indicated
- In patients with advanced phase CML or
Ph+ ALL, perform CBCs weekly for the first 2 months and then
monthly thereafter, or as clinically indicated
- Myelosuppression is generally
reversible and usually managed by withholding SPRYCEL temporarily
and/or dose reduction
- In clinical studies, myelosuppression
may have also been managed by discontinuation of study therapy
- Hematopoietic growth factor has been
used in patients with resistant myelosuppression
Bleeding-Related Events
SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+
ALL clinical studies, Grade ≥3 central nervous system (CNS)
hemorrhages, including fatalities, occurred in <1% of patients
receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage, occurred
in 5.8% of adult patients and generally required treatment
interruptions and transfusions. The incidence of Grade 5 hemorrhage
occurred in 0.4% of adult patients. The most frequent site of
hemorrhage was gastrointestinal.
- Most bleeding events in clinical
studies were associated with severe thrombocytopenia
- In addition to causing thrombocytopenia
in human subjects, dasatinib caused platelet dysfunction in
vitro
- Concomitant medications that inhibit
platelet function or anticoagulants may increase the risk of
hemorrhage
Fluid Retention
SPRYCEL may cause fluid retention. After 5 years of follow-up in
the adult randomized newly diagnosed chronic phase CML study
(n=258), grade 3/4 fluid retention was reported in 5% of patients,
including 3% of patients with grade 3/4 pleural effusion. In adult
patients with newly diagnosed or imatinib resistant or intolerant
chronic phase CML, grade 3/4 fluid retention occurred in 6% of
patients treated with SPRYCEL at the recommended dose (n=548). In
adult patients with advanced phase CML or Ph+ ALL treated with
SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention
was reported in 8% of patients, including grade 3/4 pleural
effusion reported in 7% of patients. In pediatric patients with
chronic phase CML cases of Grade 1 or 2 fluid retention were
reported in 10.3% of patients.
- Patients who develop symptoms of
pleural effusion or other fluid retention, such as new or worsened
dyspnea on exertion or at rest, pleuritic chest pain, or dry cough
should be evaluated promptly with a chest x-ray or additional
diagnostic imaging as appropriate
- Fluid retention events were typically
managed by supportive care measures that may include diuretics or
short courses of steroids
- Severe pleural effusion may require
thoracentesis and oxygen therapy
- Consider dose reduction or treatment
interruption
Cardiovascular Events
SPRYCEL can cause cardiac dysfunction. After 5 years of
follow-up in the randomized newly diagnosed chronic phase CML trial
in adults (n=258), the following cardiac adverse reactions
occurred:
- Cardiac ischemic events (3.9% dasatinib
vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib
vs 3.9% imatinib), and conduction system abnormalities, most
commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0%
imatinib). Two cases (0.8%) of peripheral arterial occlusive
disease occurred with imatinib and 2 (0.8%) transient ischemic
attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac
dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH)
SPRYCEL may increase the risk of developing PAH in adult and
pediatric patients, which may occur any time after initiation,
including after more than 1 year of treatment. Manifestations
include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be
reversible on discontinuation of SPRYCEL.
- Evaluate patients for signs and
symptoms of underlying cardiopulmonary disease prior to initiating
SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should
be permanently discontinued
QT Prolongation
SPRYCEL may increase the risk of prolongation of QTc in patients
including those with hypokalemia or hypomagnesemia, patients with
congenital long QT syndrome, patients taking antiarrhythmic
medicines or other medicinal products that lead to QT prolongation,
and cumulative high-dose anthracycline therapy
- Correct hypokalemia or hypomagnesemia
prior to and during SPRYCEL administration
Severe Dermatologic Reactions
Cases of severe mucocutaneous dermatologic reactions, including
Stevens-Johnson syndrome and erythema multiforme, have been
reported in patients treated with SPRYCEL.
- Discontinue permanently in patients who
experience a severe mucocutaneous reaction during treatment if no
other etiology can be identified
Tumor Lysis Syndrome (TLS)
TLS has been reported in patients with resistance to prior
imatinib therapy, primarily in advanced phase disease.
- Due to potential for TLS, maintain
adequate hydration, correct uric acid levels prior to initiating
therapy with SPRYCEL, and monitor electrolyte levels
- Patients with advanced stage disease
and/or high tumor burden may be at increased risk and should be
monitored more frequently
Embryo-Fetal Toxicity
Based on limited human data, SPRYCEL can cause fetal harm when
administered to a pregnant woman. Hydrops fetalis, fetal leukopenia
and fetal thrombocytopenia have been reported with maternal
exposure to SPRYCEL. Transplacental transfer of dasatinib has been
measured in fetal plasma and amniotic fluid at concentrations
comparable to those in maternal plasma.
- Advise females of reproductive
potential to avoid pregnancy, which may include the use of
effective contraception, during treatment with SPRYCEL and for 30
days after the final dose
Effects on Growth and Development in Pediatric Patients
In pediatric trials of SPRYCEL in chronic phase CML after at
least 2 years of treatment, adverse reactions associated with bone
growth and development were reported in 5 (5.2%) patients, one of
which was severe in intensity (Growth Retardation Grade 3). These 5
cases included cases of epiphyses delayed fusion, osteopenia,
growth retardation, and gynecomastia. Of these 5 cases, 1 case of
osteopenia and 1 case of gynecomastia resolved during
treatment.
Lactation
No data are available regarding the presence of dasatinib in
human milk, the effects of the drug on the breastfed child or the
effects of the drug on milk production. However, dasatinib is
present in the milk of lactating rats.
- Because of the potential for serious
adverse reactions in nursing children from SPRYCEL, breastfeeding
is not recommended during treatment with SPRYCEL and for 2 weeks
after the final dose
Drug Interactions
- Strong CYP3A4
inhibitors: The coadministration with strong CYP3A
inhibitors may increase dasatinib concentrations. Increased
dasatinib concentrations may increase the risk of toxicity. Avoid
concomitant use of strong CYP3A4 inhibitors. If concomitant
administration of a strong CYP3A4 inhibitor cannot be avoided,
consider a SPRYCEL dose reduction
- Grapefruit juice may
increase plasma concentrations of SPRYCEL and should be
avoided
- Strong CYP3A4 inducers: The
coadministration of SPRYCEL with strong CYP3A inducers may decrease
dasatinib concentrations. Decreased dasatinib concentrations may
reduce efficacy. Consider alternative drugs with less enzyme
induction potential. If concomitant administration of a strong
CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase
- St. John’s wort may
decrease plasma concentrations of SPRYCEL and should be
avoided
- Gastric Acid Reducing
Agents: The coadministration of SPRYCEL with a gastric
acid reducing agent may decrease the concentrations of dasatinib.
Decreased dasatinib concentrations may reduce efficacy.Do not
administer H2 antagonists or proton pump
inhibitors with SPRYCEL. Consider the use of antacids in place of
H2 antagonists or proton pump inhibitors. Administer the
antacid at least 2 hours prior to or 2 hours after the dose of
SPRYCEL. Avoid simultaneous administration of SPRYCEL with
antacids.
Adverse Reactions
The safety data reflects exposure to SPRYCEL at all doses tested
in clinical studies (n=2809) including 324 adult patients with
newly diagnosed chronic phase CML, 2388 adult patients with
imatinib resistant or intolerant chronic or advanced phase CML or
Ph+ ALL, and 97 pediatric patients with chronic phase CML.
The median duration of therapy in a total of 2712
SPRYCEL-treated adult patients was 19.2 months (range 0–93.2
months). Median duration of therapy in:
- 1618 adult patients with chronic phase
CML was 29 months (range 0–92.9 months)
- Median duration for 324 adult patients
in the newly diagnosed chronic phase CML trial was approximately 60
months
- 1094 adult patients with advanced phase
CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In two non-randomized trials in 97 pediatric patients with
chronic phase CML (51 patients newly diagnosed and 46 patients
resistant or intolerant to previous treatment with imatinib), the
median duration of therapy was 51.1 months (range 1.9 to 99.6
months).
In the newly diagnosed adult chronic phase CML trial, after a
minimum of 60 months of follow-up, the cumulative discontinuation
rate for 258 patients was 39%.
In the overall population of 2712 adult SPRYCEL-treated
patients, 88% of patients experienced adverse reactions at some
time and 19% experienced adverse reactions leading to treatment
discontinuation.
Among the 1618 adult SPRYCEL-treated patients with chronic phase
CML, drug-related adverse reactions leading to discontinuation were
reported in 329 (20.3%) patients.
- In the adult newly diagnosed chronic
phase CML trial, drug was discontinued for adverse reactions in 16%
of SPRYCEL-treated patients with a minimum of 60 months of
follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML
or Ph+ ALL, drug-related adverse reactions leading to
discontinuation were reported in 191 (17.5%) patients.
Among the 97 pediatric subjects, drug-related adverse reactions
leading to discontinuation were reported in 1 patient (1%).
Patients ≥65 years are more likely to experience the commonly
reported adverse reactions of fatigue, pleural effusion, diarrhea,
dyspnea, cough, lower gastrointestinal hemorrhage, and appetite
disturbance, and more likely to experience the less frequently
reported adverse reactions of abdominal distention, dizziness,
pericardial effusion, congestive heart failure, hypertension,
pulmonary edema and weight decrease, and should be monitored
closely.
- In adult newly diagnosed chronic phase
CML patients:
- Drug-related serious adverse reactions
(SARs) were reported for 16.7% of patients. Serious adverse
reactions reported in ≥5% of patients included pleural effusion
(5%)
- Grade 3/4 laboratory abnormalities
included neutropenia (29%), thrombocytopenia (22%), anemia (13%),
hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%),
and elevated creatinine (1%)
- In adult patients resistant or
intolerant to prior imatinib therapy:
- Drug-related SARs were reported for
26.1% of SPRYCEL-treated patients treated at the recommended dose
of 100 mg once daily in the randomized dose-optimization trial of
patients with chronic phase CML resistant or intolerant to prior
imatinib therapy. Serious adverse reactions reported in ≥5% of
patients included pleural effusion (10%)
- Grade 3/4 hematologic laboratory
abnormalities in chronic phase CML patients resistant or intolerant
to prior imatinib therapy who received SPRYCEL 100 mg once daily
with a minimum follow up of 60 months included neutropenia (36%),
thrombocytopenia (24%), and anemia (13%). Other grade 3/4
laboratory abnormalities included: hypophosphatemia (10%), and
hypokalemia (2%)
- Among chronic phase CML patients with
resistance or intolerance to prior imatinib therapy, cumulative
grade 3/4 cytopenias were similar at 2 and 5 years including:
neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia
(13% vs 13%)
- Grade 3/4 elevations of transaminases
or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and
hypophosphatemia were reported in patients with all phases of CML
- Elevations in transaminases or
bilirubin were usually managed with dose reduction or
interruption
- Patients developing Grade 3/4
hypocalcemia during the course of SPRYCEL therapy often had
recovery with oral calcium supplementation
- In pediatric subjects with Ph+ CML in
chronic phase
- Drug-related SARs were reported for
14.4% of pediatric patients
- In the pediatric studies, the rates of
laboratory abnormalities were consistent with the known profile for
laboratory parameters in adults
- Most common adverse reactions (≥15%) in
patients included myelosuppression, fluid retention events,
diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue,
nausea, and musculoskeletal pain
Please see full Prescribing Information
here.
About Bristol-Myers
Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that Sprycel will receive regulatory approval for additional
indications. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2017 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
References
1. American Cancer Society. “What Is Chronic Myeloid
Leukemia?” https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/what-is-cml.html.
Accessed September 18, 2017.
2. National Cancer Institute. “Chronic Myelogenous Leukemia
Treatment (PDQ®)–Patient
Version.” https://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq.
Accessed September 18, 2017.
3. American Cancer Society. “Do We Know What Causes Chronic
Myeloid
Leukemia?” https://www.cancer.org/cancer/chronic-myeloid-leukemia/causes-risks-prevention/what-causes.html.
Accessed September 18, 2017.
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Bristol-Myers SquibbMedia:Audrey Abernathy, cell:
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609-252-7509timothy.power@bms.com
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