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

February 11, 2019 6:59 AM

PRINCETON, N.J.--(BUSINESS WIRE)-- 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 ofSpryceladministered in combination with chemotherapy in pediatric patients with Ph+ ALL in the CA180-372 trial was consistent with the known safety profile ofSprycelin adults with Ph+ ALL and the known safety profile of the chemotherapy regimen. Primary toxicities of any causality included hematological toxicity such as grade 3 or 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 60mg/m2 on a continuous dosing regimen for up to 24months, 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 forSprycelin 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. Spryceltablets 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:

SPRYCEL is indicated for the treatment of pediatric patients 1 year of age and older 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.

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.

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.

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:

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.

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

Severe Dermatologic Reactions:

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Tumor Lysis Syndrome (TLS):

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

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.

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.

Drug Interactions:

Effect of Other Drugs on Dasatinib

Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2antagonists 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:

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.

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.

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 Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.

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Source: Bristol-Myers Squibb Company

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