BLINCYTO(blinatumomab) for injection为全球首个获得FDA批准的双特异性T细胞CD3结合CD19靶向抗体药物

BLINCYTO Rx
Pharmacological Class:
Bispecific CD19-directed CD3 T-cell engager.

Active Ingredient(s):
Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Company
Amgen, Inc.
Indication(s):
Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Pharmacology:
Blinatumomab binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. It mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.

Clinical Trials:
The safety and efficacy of Blincyto were eva luated in an open-label, multi-center, single-arm study (N=185). Patients were given Blincyto 9mcg/day for Week 1, then 28mcg/day for the remaining 3 weeks. The target dose of 28mcg/day was given in Cycle 2 and subsequent cycles.

The primary endpoint was complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with Blincyto. Results showed 77/185 (41.6%) patients achieved CR/CRh* within the first 2 cycles, with 81% of responses occurring within Cycle 1 of treatment.

Minimal residual disease response was seen in 75.3% of the CR/CRh* group (95% CI: 64.2–84.4). Duration of response/relapse-free survival was 6.7 months (range: 0.46–16.5) in the CR group and 5.9 months (range: 0.13–16.5) in the CR/CRh* group.

For more clinical trial data, see full labeling.

Legal Classification:
Rx

Adults:
Strictly follow preparation and administration instructions. Pre-medicate with IV dexamethasone 20mg 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. One single cycle = 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval. ≥18 years (≥45kg): Give by continuous IV infusion at a rate of 10mL/hr for 24 hours or 5mL/hr for 48 hours. Cycle 1: 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28. Subsequent cycles: 28mcg/day on Days 1–28. Treat up to a total of 5 cycles. Dose adjustments: see full labeling.

Children:
<18 years: not established.

Warnings/Precautions:
Monitor for signs/symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5XULN or if bilirubin rises >3XULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis. Elderly. Pregnancy (Category C). Nursing mothers: not recommended.

Interaction(s)
Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine.

Adverse Reaction(s)
Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity.

How Supplied:
Pack—1 (single-use vial + IV solution stabilizer)

LAST UPDATED:
3/13/2015
BLINCYTO获FDA快速批准 成为首个上市双特异性抗体
日前，安进公司获美国食品和药品监督管理局（FDA）已批准BLINCYTO（Blinatumomab）用于费城染色体阴性（Ph-）的复发性或难治性前B细胞急性淋巴细胞白血病（ALL）的治疗。该适应症按照加速审批通道获得批准。在随后的临床试验中将验证临床获益，并据此对该适应症做进一步批准。此次批准使BLINCYTO成为首个FDA批准的双特异性T细胞CD3结合CD19靶向抗体（BiTE）；同时BLINCYTO也是批准用于费城染色体阴性（Ph-）的复发性或难治性前B细胞急性淋巴细胞白血病（ALL）的首个单药免疫治疗药物。Ph-复发性或难治性B细胞前体细胞性ALL是一种罕见且进展快速的血液和骨髓肿瘤。
前体 B-cell ALL 是一种增长快速的癌症，该病患者的骨髓产生太多的 B 细胞淋巴母细胞，这种细胞是一种不成熟的白细胞。费城染色体是有时发生在白血病患者骨髓中的一种异常。美国国家癌症研究所预测，2014 年将有 6020 名美国人被确诊患有 ALL，有 1440 人将死于这种疾病。通常诊断为ALL的成人患者为青壮年，确诊时的年龄中位数为34-39岁。成人复发性或难治性ALL患者的中位总生存时间仅为3至5个月。
安进公司研发部执行副总裁Sean E. Harper医学博士指出，“FDA将BLINCYTO指定为突破性治疗并予以加速审评，这显然表明对于这种通常易发生于年轻成人患者的复发性或难治性前B细胞ALL疾病而言，目前迫切需要新的治疗选择”。Sean博士同时指出：“BiTE是一种有助于机体自身免疫系统战胜肿瘤的创新治疗方法，BLINCYTO是BiTE研究平台首次在临床和法规上的验证”。
BLINCYTO的批准基于安进公司的211临床试验的结果，该试验是一项多中心、单臂、开放标签的II期研究。合格的入选患者为：年龄≥18岁，费城染色体阴性的复发性或难治性前B细胞ALL的患者。复发性或难治性的定义为首次治疗后首次缓解时间小于12个月的复发者，或首次挽救治疗后复发或难治，或进行异体造血干细胞移植 (HSCT) 后12个月内复发，且骨髓中原始细胞≥10%。在临床试验评价的185例患者中，41.6% (77/185; 95% CI: 34.4-49.1) 的患者在2个BLINCYTO治疗周期内达到完全缓解或完全缓解伴部分血液学缓解 (CR/CRh*)，这也是该研究的首要终点。大多数缓解 (81% [62/77]) 发生于第1周期的治疗。达到CR/CRh*的患者中，39% (30/77) 进行了HSCT，75.3% (58/77; 95% CI: 64.2-84.4) 达到最小残留病灶 (MRD)的缓解，MRD是分子水平的残留病灶的根除指标。
希望之城（City of Hope）的血液学/肿瘤学临床教授Anthony S. Stein博士指出：“BLINCYTO获得批准代表免疫治疗研究取得了重要的里程碑式进步，BLINCYTO给临床医师提供了一种新的单药治疗的机会帮助患者战胜此类既往治疗选择有限且高度侵袭的肿瘤疾病”。