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

百时美施贵宝 Sproyce 联合化疗方法获欧盟批准

2019-02-12 17:28:03 BioSpace

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PRINCETON, N.J.---- Bristol-Myers Squibb Company today announced that the European Commission has approved Sprycel in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia . 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 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 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 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 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 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 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 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%) 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%) 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 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 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%) 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 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" within the meaning of the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. No forward-looking statement can be guaranteed. 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, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by federal securities law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. View source version on businesswire.com: https://www.businesswire.com/news/home/20190211005351/en/ Media: Kirby Hosea, 609-302-4399 kirby.hosea@bms.com Investor: Bill Szablewski, 609-252-5894 william.szablewski@bms.com Tim Power, 609-252-7509 timothy.power@bms.com Source: Bristol-Myers Squibb Company View this news release online at: http://www.businesswire.com/news/home/20190211005351/en
百时美施贵宝(Bristol-Myers Squibb)公司今天宣布,欧盟委员会已批准 Spycel 联合化疗,用于治疗新诊断的费城染色体阳性急性淋巴细胞白血病患儿。这是欧洲第二个儿童白血病适应症。该批准包括 Spycel 的片剂形式和欧洲 ALL 患儿的第一个口服 Spycel 悬浮剂。 “我们感到自豪的是,欧盟委员会的批准给患有 Ph +急性淋巴细胞白血病的儿童带来了一种新的治疗选择,包括一种粉剂配方,作为我们致力于解决儿童癌症的独特需求的一部分,”百时美施贵宝(Bristol-Myers Squibb)肿瘤学发展部主任 Fouad Namouni 说。 批准的依据是 CA180-372( NCT01460160)的数据,这是第二阶段的试验,该试验评估了 Spycel 加入化疗养生法的情况,该方案是在新近诊断为 Ph + ALL 的儿科患者中,以柏林-法兰克福- Munster 为模型的高风险骨干。2017年美国血液学会年会上公布的 CA180-372试验结果显示,在三年时间里, Spycel 和化疗的结合显示无事件生存率( EFS )为65.5%(95% CI :57.7-73.7),整体生存率为91.5%(95% CI :84.2-95.5)。 CA180-372试验中, Spycel 与 Ph + ALL 患儿化疗联合应用的安全性概况与已知的 Spycel 成人 Ph + ALL 安全性概况和已知的化疗养生法安全性概况一致。任何因果关系的主要毒性包括血液学毒性,如3级或4级发热中性粒细胞减少(75.5%)、败血症(23.6%)和菌血症(24.5%)。10%以上患者非血液学、非感染性3级或4级不良事件( AE )仅限于丙氨酸转氨酶升高(21.7%)和门冬氨酸转氨酶升高(10.4%)。其他3级或4级不良反应为胸腔积液(3.8%)、水肿(2.8%)、出血(5.7%)和心力衰竭(0.8%)。没有报告肺动脉高压或肺动脉高压的事件。 研究中接受治疗的患者( n =106),年龄均小于18岁,在连续24个月的连续给药养生法中每天服用60毫克/平方米的 Spycel ,并与化疗联合使用。77%的患者( N =82)仅接受 Spycel 片剂,23%的患者( N =24)至少接受一次 Spycel 全氟辛烷磺酸。 建议开始剂量的 Spycel 在儿科患者的 Ph + ALL 是根据体重。Spycel 全氟辛烷磺酸适用于体重10公斤或以下,或不能吞咽整个片剂的患者。片剂和全氟辛烷磺酸制剂的推荐剂量应每三个月根据体重变化重新计算一次,必要时可更经常地重新计算。喷雾剂片剂应全部吞咽,不得压碎、切碎或咀嚼。接受压碎药片的病人的接触量低于那些吞咽完整药片的病人。Spycel 片剂和全氟辛烷磺酸制剂不具有生物等效性。患者只应根据医生的判断在片剂和全氟辛烷磺酸制剂之间切换,医生将根据患者的体重决定正确的制剂和剂量。 百时美施贵宝:肿瘤研究的进展 在百时美施贵宝(Bristol-Myers Squibb),病人是我们所做一切的中心。我们的研究重点是提高癌症患者的质量,长期生存,使治愈成为可能。通过以转化科学为动力的独特的多学科方法,我们利用我们在肿瘤学和免疫肿瘤学( I-O )研究方面的深厚科学经验,确定适合个人患者需求的新疗法。我们的研究人员正在开发一个多样化的,有目的地建立管道,旨在针对不同的免疫系统路径,并解决复杂和具体的相互作用之间的肿瘤,其微环境和免疫系统。我们在内部和与学术界、政府、倡导团体和生物技术公司合作,寻求创新,以帮助实现像 I-O 这样的变革性药物,成为患者的现实。 关于虫草 Spycel 是第二代酪氨酸激酶抑制剂( TKI ),旨在帮助抑制 BCR-ABL ,一种在费城染色体突变中发现的异常蛋白,大多数慢性粒细胞白血病( CML )和 ALL 患者,这可能触发受损或不成熟的白细胞的生产过剩。通过对 BCR-ABL 蛋白的靶向治疗, Spycel 可以减少体内受损白细胞的数量,从而产生更正常的细胞。 Spycel 目前已在60多个国家获得批准用于治疗慢性阶段( CP-CML )有 Ph + ALL 或 Ph + CML 耐药或不耐受的成人,以及在50多个国家用于治疗新诊断的 Ph + CP-CML 成人。2017年, Spycel 成为第一个获得批准用于治疗1岁及以上 Ph + CP-CML 患者的第二代 TKI 患者时,获得了其第一个儿科适应症。Spycel 还被批准与化疗联合治疗小儿新诊断的 Ph + ALL 患者。 在欧洲, Spryl 的两个儿科适应症都包括全氟辛烷磺酸制剂,其批准使 Spryl 成为第一个拥有批准的给付给 Ph + CP-CML 和 Ph + ALL 儿科患者的粉剂制剂的 TKI 。全氟辛烷磺酸制剂也被批准用于不能吞咽片剂的成年患者+ CP-CML 。 美国 FDA 批准 SPRYCEL ® SPRYCEL ®(达沙替尼)用于治疗成人患者: 慢性粒细胞白血病( CML )的新诊断 慢性、加速或髓样或淋巴细胞期 Ph + CML ,对包括伊马替尼在内的先前治疗具有耐药性或不耐受 费城染色体阳性急性淋巴细胞性白血病( Ph + ALL )对先前治疗有耐药性或不耐受 SPRYCEL 适用于1岁及以上儿童患者的治疗: 慢性阶段博士+ CML 新诊断的 Ph + ALL 联合化疗 重要的安全资料 骨髓抑制: SPRYCEL 的治疗与严重( NCI CTCAE 3/4级)血小板减少、中性粒细胞减少和贫血有关,在晚期 CML 或 Ph + ALL 患者中发生的时间和频率比慢性期 CML 患者早。有正常基线标准值的患者和先前存在实验室异常的患者均报告有骨髓抑制。 对于慢性期 CML 患者,每2周进行一次完整的血液计数( CBC ),持续12周,此后每3个月进行一次,或者如临床所示 在晚期 CML 或 Ph + ALL 患者中,在头2个月每周进行 CBC 治疗,然后每月进行一次,或者如临床所示 在接受 SPRYCEL 联合化疗治疗的患儿中,在开始每一块化疗前进行 CBC ,临床表现为。在化疗的巩固阶段,每2天进行一次化疗,直到痊愈 骨髓抑制通常是可逆的,通常通过暂时停用 SPRYCEL 和/或减少剂量来管理 在临床研究中,骨髓抑制可能也是通过停止研究治疗来管理的 造血生长因子已被用于耐骨髓抑制患者 造血生长因子已被用于耐骨髓抑制患者 出血相关事件: SPRYCEL 可导致严重和致命的出血。在所有 CML 或 Ph + ALL 临床研究中,分级≥3级中枢神经系统出血(包括死亡)发生在 SPRYCEL 患者<1%。3/4级出血的发生率发生在5.8%的成人患者,一般需要治疗中断和输血。成人5级出血发生率为0.4%.最常见的出血部位是胃肠。 临床研究中的大部分出血事件与严重血小板减少有关 除了引起人体血小板减少外,达沙替尼还在体外引起血小板功能障碍 抑制血小板功能或抗凝血剂的药物可能会增加出血的风险 流体保留: SPRYCEL 可引起液体潴留。在成人随机新诊断的慢性 CML 研究( n =258)中随访5年后,5%的患者报告3/4级液体潴留,其中3/4级胸腔积液患者占3%。在新诊断或伊马替尼耐药或不耐受的慢性 CML 成人患者中,6%接受 SPRYCEL 治疗的患者在推荐剂量( n =548)时出现3/4级液体潴留。在接受 SPRYCEL 推荐剂量( n =304)治疗的晚期 CML 或 Ph + ALL 成年患者中,8%的患者报告3/4级液体潴留,其中7%的患者报告3/4级胸腔积液。在慢性 CML 患儿中,10.3%的患者报告1级或2级液体潴留。 出现胸腔积液或其他液体潴留症状的患者,如劳累或休息时出现新的或恶化的呼吸困难、胸腔疼痛或干咳等,应及时用胸部 X 线或附加诊断影像进行评估 液体保留事件通常通过支持性护理措施进行管理,这些措施可能包括利尿剂或短程类固醇 严重胸腔积液可能需要胸腔和氧气治疗 考虑剂量减少或治疗中断 心血管事件: SPRYCEL 可引起心脏功能障碍。成人随机新诊断慢性期 CML 试验随访5年后( n =258),发生如下心脏不良反应: 心脏缺血事件(3.9%达沙替尼,1.6%伊马替尼),心脏相关液体滞留(8.5%达沙替尼,3.9%伊马替尼),传导系统异常,最常见的心律失常和心悸(7.0%达沙替尼,5.0%伊马替尼)。伊马替尼2例(0.8%)外周动脉闭塞性疾病,达沙替尼2例(0.8%)短暂缺血发作 监测患者是否有与心脏功能障碍相一致的体征或症状,并适当治疗。 肺动脉高压( PAH ): SPRYCEL 可增加成人和儿童患者发生 PAH 的风险,可能发生在启动后的任何时间,包括超过1年的治疗后。表现包括呼吸困难、疲劳、缺氧和液体滞留。停用 SPRYCEL 可逆转 PAH 。 在开始 SPRYCEL 之前和治疗期间评估患者潜在的心肺疾病的症状和体征。如果确认 PAH , SPRYCEL 应永久停止 QT 延长: SPRYCEL 可能会增加 QTc 延长的风险,包括低钾血症或低镁血症患者、先天性长 QT 综合征患者、服用抗心律失常药物或其他导致 QT 延长的药物的患者,以及累积高剂量蒽环类药物治疗 在 SPRYCEL 给药前后纠正低钾血症或低镁血症 严重的皮肤反应: 在 SPRYCEL 治疗的患者中,报告了严重的粘液性皮肤反应,包括 Stevens-Johnson 综合征和红斑多形性红斑。 如果不能确定其他病因,在治疗过程中发生严重粘液反应的患者永久停药 肿瘤淋巴瘤综合征( TLS ): TLS 已被报道在对伊马替尼治疗前耐药的患者中,主要是在晚期疾病。 由于 TLS 的潜力,保持足够的水化,在开始使用 SPRYCEL 治疗前纠正尿酸水平,并监测电解质水平 晚期疾病和/或高肿瘤负担的患者可能面临更高的风险,应更频繁地进行监测 胚胎-胎儿毒性: 根据有限的人体资料, SPRYCEL 在给孕妇服用时会造成胎儿伤害。胎儿积水、胎儿白细胞减少和胎儿血小板减少已报告母亲接触 SPRYCEL 。在胎儿血浆和羊水中检测到达沙替尼的胎盘转移,浓度与母体血浆相当。 建议有生育潜力的女性避免怀孕,包括在 SPRYCEL 治疗期间和最后一次剂量后30天使用有效的避孕方法 对儿科患者生长发育的影响: 在治疗至少2年后的慢性期 CML 小儿试验中,5例(5.2%)患者报告了与骨生长发育相关的不良反应,其中1例严重(生长迟缓3级)。这5例包括表皮炎延迟融合、阴茎骨化、生长迟缓和妇科乳腺炎。在这5例中,1例骨性阴茎和1例妇科乳腺炎在治疗中得到了解决。 监测儿童骨骼的生长和发育。 哺乳期: 目前还没有关于达沙替尼在母乳中的存在、该药物对母乳喂养孩子的影响或该药物对牛奶生产的影响的数据。然而,在哺乳大鼠的牛奶中存在达沙替尼。 由于 SPRYCEL 患儿可能出现严重不良反应,因此在 SPRYCEL 治疗期间和最后一次剂量后2周内不建议母乳喂养 药物相互作用: 其他药物对达马替尼的影响 强 CYP3A4抑制剂:强 CYP3A 抑制剂的联合应用可增加达沙替尼浓度。增加达沙替尼浓度可能增加毒性风险。避免同时使用强 CYP3A4抑制剂。如果不能避免同时给予强 CYP3A4抑制剂,考虑降低 SPRYCEL 剂量 葡萄柚汁可以增加血浆中 SPRYCEL 的浓度,应该避免 葡萄柚汁可以增加血浆中 SPRYCEL 的浓度,应该避免 强 CYP3A4诱导剂:强 CYP3A 诱导剂对 SPRYCEL 的协同作用可降低达沙替尼浓度。减少达沙替尼浓度可降低疗效。考虑具有较少酶诱导潜能的替代药物。如果不能避免同时给予强 CYP3A4诱导剂,考虑 SPRYCEL 剂量增加 圣。John 的虫子可以降低 SPRYCEL 的血浆浓度,应该避免 圣。John 的虫子可以降低 SPRYCEL 的血浆浓度,应该避免 胃酸还原剂: SPRYCEL 与胃酸还原剂合用可降低达沙替尼的浓度。减少达沙替尼浓度可降低疗效。 不要给 H2拮抗剂或质子泵抑制剂与 SPRYCEL 。考虑使用抗酸剂代替 H2拮抗剂或质子泵抑制剂。在服用 SPRYCEL 前至少2小时或2小时后服用抗酸剂。避免同时给药 SPRYCEL 。 常见的不良反应: 这些安全数据反映了在临床研究中( n =2809)测试的所有剂量下使用 SPRYCEL 作为单一药物治疗的暴露情况,包括324名新诊断的慢性阶段 CML 的成人患者、2388名耐伊马替尼或晚期 CML 或 Ph + ALL 的成人患者以及97名慢性阶段 CML 的儿童患者。 接受 SPRYCEL 治疗的成人患者中位治疗时间为19.2个月(范围0-93.2个月)。中位治疗时间: 1618例慢性期 CML 成人患者29个月(范围0-92.9个月) 在新诊断的慢性 CML 试验中,324名成人患者的中位生存期约为60个月 在新诊断的慢性 CML 试验中,324名成人患者的中位生存期约为60个月 1094例晚期 CML 或 Ph + ALL 的成人患者为6.2个月(范围0-93.2个月) 在97例慢性期 CML 患儿(51例新诊断,46例对伊马替尼前期治疗耐药或不耐受)的两项非随机试验中,治疗的中位期为51.1个月(1.9至99.6个月)。 对81例新诊断的 Ph + ALL 患儿进行 SPRYCEL 连续多药联合化疗的多组研究中,平均疗程为24个月(2~27个月)。 在新诊断的成人慢性期 CML 试验中,随访至少60个月后,258例患者的累计停药发生率为39%。 在2712例成年患者的总体人群中,88%的患者在一段时间内出现不良反应,19%的患者出现不良反应导致治疗中断。 在1618例慢性期 CML 成人患者中,329例(20.3%)患者报告了导致停药的药物相关不良反应。 在成人新诊断的慢性期 CML 试验中,至少60个月随访的 SPRYCEL 治疗患者中有16%的患者因不良反应停用了药物 在1094例晚期 CML 或 Ph + ALL 患者中,191例(17.5%)患者报告了导致停药的药物相关不良反应。 在97例 CML 患儿中,1例(1%)报告了导致停药的药物相关不良反应。 年龄≥65岁的患者更容易出现疲劳、胸腔积液、腹泻、呼吸困难、咳嗽、胃肠道出血较低、食欲紊乱等常见不良反应,更可能出现较少报告的腹胀、头晕、心包积液等不良反应。充血性心力衰竭、高血压、肺水肿、体重减轻,应密切监测。 成人新诊断慢性期 CML 患者: 16.7%的患者报告了药物相关的严重不良反应。严重不良反应报告≥5%患者包括胸腔积液(5%) 3/4级实验室异常包括中性粒细胞减少(29%)、血小板减少(22%)、贫血(13%)、低磷血症(7%)、低钙血症(4%)、高胆红素(1%)和高肌酐(1%)。 16.7%的患者报告了药物相关的严重不良反应。严重不良反应报告≥5%患者包括胸腔积液(5%) 3/4级实验室异常包括中性粒细胞减少(29%)、血小板减少(22%)、贫血(13%)、低磷血症(7%)、低钙血症(4%)、高胆红素(1%)和高肌酐(1%)。 成人患者对伊马替尼治疗前耐药或不耐受: 在对早期伊马替尼治疗的慢性 CML 耐药或不耐受患者的随机剂量优化试验中,26.1%的 SPRYCEL 治疗患者每天接受100毫克的推荐剂量治疗。严重不良反应报告≥5%患者包括胸腔积液(10%) 慢性 CML 患者在接受 SPRYCEL 100mg 每日一次,最低随访60个月后出现3/4级血液实验室异常,这些患者对以往伊马替尼治疗耐药或不耐受,包括中性粒细胞减少(36%)、血小板减少(24%)和贫血(13%)。其他3/4级实验室异常包括:低磷血症(10%)和低钾血症(2%)。 在早期伊马替尼治疗耐药或不耐受的慢性期 CML 患者中,2年和5年内累积的3/4级细胞减少症相似,包括:中性粒细胞减少症(36% vs36%)、血小板减少症(23% vs24%)和贫血(13% vs13%) 在对早期伊马替尼治疗的慢性 CML 耐药或不耐受患者的随机剂量优化试验中,26.1%的 SPRYCEL 治疗患者每天接受100毫克的推荐剂量治疗。严重不良反应报告≥5%患者包括胸腔积液(10%) 慢性 CML 患者在接受 SPRYCEL 100mg 每日一次,最低随访60个月后出现3/4级血液实验室异常,这些患者对以往伊马替尼治疗耐药或不耐受,包括中性粒细胞减少(36%)、血小板减少(24%)和贫血(13%)。其他3/4级实验室异常包括:低磷血症(10%)和低钾血症(2%)。 在早期伊马替尼治疗耐药或不耐受的慢性期 CML 患者中,2年和5年内累积的3/4级细胞减少症相似,包括:中性粒细胞减少症(36% vs36%)、血小板减少症(23% vs24%)和贫血(13% vs13%) 3/4级转氨酶或胆红素升高,3/4级低钙血症,低钾血症和低磷血症在所有阶段的 CML 患者中均有报道 转氨酶或胆红素的升高通常以剂量减少或中断的方式进行管理 在 SPRYCEL 治疗过程中出现3/4级低钙血症的患者常有口服补钙恢复 转氨酶或胆红素的升高通常以剂量减少或中断的方式进行管理 在 SPRYCEL 治疗过程中出现3/4级低钙血症的患者常有口服补钙恢复 慢性阶段 Ph + CML 患儿 据报道,14.4%的儿童患者使用了药物相关的 SAR 5例(5.2%)慢性 CML 患儿出现骨生长发育不良反应 在儿科研究中,实验室异常的发生率与成人实验室参数的已知资料一致 据报道,14.4%的儿童患者使用了药物相关的 SAR 5例(5.2%)慢性 CML 患儿出现骨生长发育不良反应 在儿科研究中,实验室异常的发生率与成人实验室参数的已知资料一致 应用 SPRYCEL 联合多药化疗治疗小儿 Ph + ALL 患者 3例(4%)发生致命不良反应,均为感染所致 8例(10%)患者出现不良反应导致停止治疗 最常见的严重不良反应(发病率≥10%)为发热、中性粒细胞减少、粘膜炎、腹泻、败血症、低血压、感染(细菌、病毒和真菌)、过敏症、呕吐、肾功能不全、腹痛和肌肉骨骼疼痛 3/4级实验室异常(≥10%)包括中性粒细胞减少(96%)、血小板减少(88%)、贫血(82%)、 SGPT 升高( ALT )(47%)、低钾血症(40%)、 SGOT 升高( AST )(26%)、低钙血症(19%)、低钠血症(19%)、高胆红素(11%)和低磷血症(11%)。 3例(4%)发生致命不良反应,均为感染所致 8例(10%)患者出现不良反应导致停止治疗 最常见的严重不良反应(发病率≥10%)为发热、中性粒细胞减少、粘膜炎、腹泻、败血症、低血压、感染(细菌、病毒和真菌)、过敏症、呕吐、肾功能不全、腹痛和肌肉骨骼疼痛 3/4级实验室异常(≥10%)包括中性粒细胞减少(96%)、血小板减少(88%)、贫血(82%)、 SGPT 升高( ALT )(47%)、低钾血症(40%)、 SGOT 升高( AST )(26%)、低钙血症(19%)、低钠血症(19%)、高胆红素(11%)和低磷血症(11%)。 在接受 SPRYCEL 作为单一药物治疗的患者中,最常见的不良反应(≥15%)包括骨髓抑制、液体滞留事件、腹泻、头痛、皮疹、出血、呼吸困难、疲劳、恶心和肌肉骨骼疼痛。 接受 SPRYCEL 联合化疗的儿科患者最常见的不良反应(≥30%)包括:粘膜炎、发热中性粒细胞减少、发热、腹泻、恶心、呕吐、肌肉骨骼疼痛、腹痛、咳嗽、头痛、皮疹、疲劳、便秘、心律失常、高血压、水肿、感染(细菌、病毒和真菌)、低血压、食欲下降、过敏症、呼吸困难、鼻出血、周围神经病变和意识状态改变 请参阅全部压力资料。 SPRYCEL ®是百时美施贵宝公司的商标。 关于百时美施贵宝(Bristol-Myers Squibb) 百时美施贵宝( Bristol-MyersSquibb )是一家全球性生物制药公司,其使命是发现、开发和提供创新药物,帮助患者战胜严重疾病。有关百时美施贵宝(Bristol-Myers Squibb)的更多信息,请访问 BMS.com 或在 LinkedIn 、 Twitter 、 YouTube 和 Facebook 上关注我们。 百时美施贵宝前瞻性声明 本新闻稿包含1995年《私人证券诉讼改革法案》中关于医药产品研究、开发和商业化的“前瞻性陈述”。并非历史事实陈述的所有陈述均为或可能被视为前瞻性陈述。该等前瞻性陈述乃基于过往业绩及目前对我们未来财务业绩、目标、计划及目标的预期及预测,并涉及固有风险、假设及不明朗因素,包括可能于未来数年内延迟、转移或改变其中任何一项的内部或外部因素;并可能导致我们未来的财务业绩、目标、计划及目标与该等报表所表达或隐含的财务业绩、目标、计划及目标存在重大差异。无法保证前瞻性声明。本新闻稿中的前瞻性陈述应与影响百时美施贵宝业务的许多不确定性一起进行评估,特别是在百时美施贵宝截至2017年12月31日止年度的10-K 表格年度报告中的警示因素讨论中发现的不确定性。由我们随后的10-Q 季报、8-K 季报及向证券交易委员会提交的其他文件更新。本文件中包含的前瞻性陈述仅于本文件日期作出,除联邦证券法另有规定外,百时美施贵宝不承担因新信息、未来事件而公开更新或修订任何前瞻性声明的义务。改变情况或其他。 查看 businesswire 上的源代码。com : https://www.businesswire.com/news/home/2019021005351/en/ 媒体: Kirby Hosea ,609-302-4399 柯比。软管@ bms.com 出资人: Bill Szablewski ,609-252-5894 威廉。szablewski @ bms.com Tim Power ,609-252-7509 东帝汶。power @ bms.com 资料来源:百时美施贵宝公司 在线查看本新闻稿,网址为: http://www.businesswire.com/news/home/2019021005351/en

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