U.S. Food and Drug Administration Accepts Bristol-Myers Squibb?s Application for Sprycel (dasatinib) in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphobl
PRINCETON, N.J.-Bristol-Myers Squibb Company?(NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) accepted its supplemental Biologics License Application (sBLA) for?Sprycel?(dasatinib) in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The FDA action date is December 29, 2018.
?Sprycel?was first established as an important treatment option for appropriate pediatric patients last year, when it was approved for the treatment of children with Ph+ chronic myeloid leukemia,? said Jeffrey Jackson, Ph.D., development lead, hematology, Bristol-Myers Squibb. ?This latest milestone in Ph+ ALL reinforces our commitment to researching the potential of?Sprycel?in different types of pediatric leukemia and to providing this vulnerable population with access to potential new therapies.?
The application is based on data from CA180-372 (NCT01460160), an ongoing Phase 2 trial evaluating 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.
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 is approved for this indication in more than 50 countries.
Both the FDA and the European Commission approved the expansion of?Sprycel?s?indication to include pediatric patients with Ph+ CML-CP in November 2017 and July 2018.
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
- Ph+ CML in chronic phase
- 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
- 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
- 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
- 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
- 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
- Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
- Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
- 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
- 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
- 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
- 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.
- 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 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
- 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
CONTACT:
FOR BRISTOL-MYERS SQUIBB
MEDIA:
DANIELLE HALSTROM, 215-280-3898
DANIELLE.HALSTROM@BMS.COM
OR
INVESTOR:
BILL SZABLEWSKI, 609-252-5894
WILLIAM.SZABLEWSKI@BMS.COM
OR
TIM POWER, 609-252-7509
TIMOTHY.POWER@BMS.COM