European Commission Approves Bristol-Myers Squibb’s Sprycel (dasatinib) in Combination with Chemotherapy for Treatment of Pediatric Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

PRINCETON, N.J.–(BUSINESS WIRE)–lt;a href=”https://twitter.com/search?q=%24BMY&src=ctag” target=”_blank”gt;$BMYlt;/agt; lt;a href=”https://twitter.com/hashtag/ALL?src=hash” target=”_blank”gt;#ALLlt;/agt;–Bristol-Myers
Squibb Company
(NYSE: BMY) today announced that the European
Commission (EC) has approved Sprycel (dasatinib) in combination
with chemotherapy for the treatment of pediatric patients with newly
diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic
leukemia (ALL). This is the second pediatric leukemia indication for Sprycel
in Europe. The approval includes both the tablet form of Sprycel and,
in a first for pediatric patients with ALL in Europe, the powder for
oral suspension (PFOS) formulation of Sprycel.

“We are proud that the approval by the European Commission brings
children with Ph+ acute lymphoblastic leukemia a new treatment option,
including a powder formulation developed as part of our commitment to
addressing the unique needs of children with cancer,” said Fouad
Namouni, M.D., head, oncology development, Bristol-Myers Squibb.

The approval is based on data from CA180-372 (NCT01460160), a Phase 2
trial which evaluated the addition of Sprycel to a chemotherapy
regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone in
pediatric patients with newly diagnosed Ph+ ALL. Results from the
CA180-372 trial presented at the 2017 American Society of Hematology
Annual Meeting showed that at three years, the combination of Sprycel and
chemotherapy demonstrated an event-free survival (EFS) rate, the study’s
primary endpoint, of 65.5% (95% CI: 57.7 to 73.7), and an overall
survival (OS) rate of 91.5% (95% CI: 84.2 to 95.5).

The safety profile of Sprycel administered in
combination with chemotherapy in pediatric patients with Ph+ ALL in the
CA180-372 trial was consistent with the known safety profile of Sprycel in
adults with Ph+ ALL and the known safety profile of the chemotherapy
regimen. Primary toxicities of any causality included hematological
toxicity such as grade 3or 4 febrile neutropenia (75.5%),
sepsis (23.6%) and bacteremia (24.5%). Non-hematologic, non-infectious
grade 3 or 4 adverse events (AEs) attributed to Sprycel and
reported in more than 10% of patients were limited to elevated alanine
aminotransferase (21.7%) and aspartate transaminase (10.4%). Other grade
3 or 4 AEs attributed to Sprycel were pleural effusion (3.8%),
edema (2.8%), hemorrhage (5.7%) and cardiac failure (0.8%). No events of
pulmonary hypertension or pulmonary arterial hypertension were reported.

Patients treated in the study (n=106), all aged younger than 18 years,
received Sprycel at a daily dose of 60 mg/m2 on a
continuous dosing regimen for up to 24 months, in combination with
chemotherapy. Seventy-seven percent of patients (N=82) received
Sprycel
tablets exclusively, and 23% of patients (N=24) received Sprycel
PFOS at least once.

The recommended starting dosage for Sprycel in pediatric
patients with Ph+ ALL is based on body weight. The Sprycel 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.

Bristol-Myers Squibb: Advancing Oncology
Research

At Bristol-Myers Squibb, patients are at the center of everything we do.
The focus of our research is to increase quality, long-term survival for
patients with cancer and make cure a possibility. Through a unique
multidisciplinary approach powered by translational science, we harness
our deep scientific experience in oncology and Immuno-Oncology (I-O)
research to identify novel treatments tailored to individual patient
needs. Our researchers are developing a diverse, purposefully built
pipeline designed to target different immune system pathways and address
the complex and specific interactions between the tumor, its
microenvironment and the immune system. We source innovation internally
and in collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of transformational
medicines, like I-O, a reality for patients.

About Sprycel

Sprycel is a second-generation tyrosine kinase inhibitor (TKI)
designed to help inhibit BCR-ABL, an abnormal protein found on the
mutated Philadelphia chromosome in most patients with chronic myeloid
leukemia (CML) and some patients with ALL, which can trigger the
overproduction of damaged or immature white blood cells. By targeting
the BCR-ABL protein, Sprycel can reduce the number of damaged
white blood cells in the body, allowing for the production of more
normal cells.

Sprycel is currently approved in more than 60 countries for the
treatment of adults with Ph+ ALL or Ph+ CML in chronic phase (CP-CML)
who are resistant or intolerant to prior therapy, and in more than 50
countries for the treatment of adults with newly diagnosed Ph+ CP-CML.
In 2017, Sprycel received its first pediatric indication when it
became the first second-generation TKI approved for the treatment
of patients one year of age and older with Ph+ CP-CML. Sprycel is
also approved in combination with chemotherapy for the treatment of
pediatric patients with newly diagnosed Ph+ ALL.

In Europe, both pediatric indications for Sprycel include the
PFOS formulation, the approvals of which made Sprycel the first
TKI with an approved powder formulation for administration in pediatric
patients with Ph+ CP-CML and Ph+ ALL. The PFOS formulation is also
approved for adult patients with Ph+ CP-CML who cannot swallow tablets.

U.S. FDA APPROVED INDICATIONS FOR SPRYCEL®

SPRYCEL® (dasatinib) is indicated for the treatment of adult
patients 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 is indicated for the treatment of pediatric patients 1 year of
age and older with:

  • Ph+ CML in chronic phase
  • Newly diagnosed Ph+ ALL in combination with chemotherapy

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
  • In pediatric patients with Ph+ ALL treated with SPRYCEL in combination
    with chemotherapy, perform CBCs prior to the start of each block of
    chemotherapy and as clinically indicated. During the consolidation
    blocks of chemotherapy, perform CBCs every 2 days until recovery
  • 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.

Monitor bone growth and development in pediatric patients.

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:

Effect of Other Drugs on Dasatinib

  • 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.

Common Adverse Reactions:

The safety data reflects exposure to SPRYCEL administered as
single-agent therapy 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 a multicohort study of SPRYCEL administered continuously in
combination with multiagent chemotherapy in 81 pediatric patients with
newly diagnosed Ph+ ALL, the median duration of therapy was 24 months
(range 2 to 27 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 patients, 88% of patients
experienced adverse reactions at some time, and 19% experienced adverse
reactions leading to treatment discontinuation.

Among the 1618 adult 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 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 CML 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
    • Adverse reactions associated with bone growth and development were
      reported in 5 (5.2%) of pediatric patients with chronic phase CML
    • In the pediatric studies, the rates of laboratory abnormalities
      were consistent with the known profile for laboratory parameters
      in adults
  • In pediatric subjects with Ph+ ALL who were administered SPRYCEL in
    combination with multiagent chemotherapy

    • Fatal adverse reactions occurred in 3 patients (4%), all of which
      were due to infections
    • Eight patients (10%) experienced adverse reactions leading to
      treatment discontinuation
    • The most common serious adverse reactions (incidence ≥10%) were
      pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis,
      hypotension, infections (bacterial, viral and fungal),
      hypersensitivity, vomiting, renal insufficiency, abdominal pain,
      and musculoskeletal pain
    • Grade 3/4 laboratory abnormalities (≥10%) included neutropenia
      (96%), thrombocytopenia (88%), anemia (82%), elevated SGPT (ALT)
      (47%), hypokalemia (40%), elevated SGOT (AST) (26%), hypocalcemia
      (19%), hyponatremia (19%), elevated bilirubin (11%), and
      hypophosphatemia (11%)

Most common adverse reactions (≥15%) in patients receiving SPRYCEL as
single-agent therapy included myelosuppression, fluid retention events,
diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and
musculoskeletal pain.

Most common adverse reactions (≥30%) in pediatric patients receiving
SPRYCEL in combination with chemotherapy included mucositis, febrile
neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain,
abdominal pain, cough, headache, rash, fatigue, constipation,
arrhythmia, hypertension, edema, infections (bacterial, viral and
fungal), hypotension, decreased appetite, hypersensitivity, dyspnea,
epistaxis, peripheral neuropathy, and altered state of consciousness

Please see full Prescribing
Information
.

SPRYCEL® is a trademark of Bristol-Myers Squibb Company.

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
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Contacts

Media:
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kirby.hosea@bms.com

Investor:
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Tim
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timothy.power@bms.com

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