简介：

近日，新型抗癌药Copiktra(duvelisib)美国获批用于既往至少有过两种治疗的复发或难治性慢性淋巴细胞性白血病/淋巴细胞性淋巴瘤。这款药物是一种磷脂酰肌醇3激酶(PI3K)抑制剂，是获批的首个PI3K-δ和PI3K-γ双重抑制剂。美国FDA还加速批准Copiktra(duvelisib)用于治疗既往至少有过两种系统性治疗的复发或难治性滤泡性淋巴瘤成人患者治疗。Copiktra加速获批用于滤泡性淋巴瘤是基于其总有效率数据，用于该适应证的后续批准可能要视该药物在验证性临床试验中获益的证据和描述。Sarah Cannon研究所淋巴瘤研究项目主任兼DYNAMO和DUO研究主要研究者Flin 称：对于复发或难治性慢性淋巴细胞性白血病/淋巴细胞性淋巴瘤与滤泡性淋巴瘤患者来说，Copiktra是不断升级的治疗范式的补充。Copiktra是医师治疗方案的一个重要补充，对于使用两种疗法后疾病恶化且治疗选择有限的患者，该药物可以解决一个未满足的需求。批准日期：2018年9月25日公司：VerastemCOPIKTRA(duvelisib)胶囊，供口服使用首次美国批准：2018警告：致命和严重毒性：感染、腹泻或结肠炎、皮肤反应和肺炎参见完整的处方信息31%的患者发生致命和/或严重感染。监测感染的体征和症状。如果怀疑感染，请保留科普特拉。在18%例COPIKTRA患者中发生致死性和/或严重腹泻或结肠炎。监测重症或结肠炎的发展。在5%例COPIKTRA患者中发生致命和/或严重皮肤反应。5%的COPD患者发生致命性和/或严重肺炎。监测肺症状和间质浸润。

作用机理：DuVISIB是PI3K抑制剂，其抑制活性主要与PI3K-δ有关。在正常和恶性B细胞中表达PI3K-γ异构体。杜维利斯诱导生长来源于恶性B细胞和原代CLL的细胞系的抑制和活力降低肿瘤细胞。Duvelisib抑制多种关键细胞信号通路，包括B细胞受体信号转导和CXCR12介导的恶性B细胞趋化作用。此外，杜维利斯抑制CXCL12诱导的T细胞迁移和M-CSF和IL-4驱动的M2极化巨噬细胞

适应症及用法：CopikTRA是一种激酶抑制剂，用于治疗成人患者：至少两次治疗前复发或难治性慢性淋巴细胞白血病(CLL)或小淋巴细胞淋巴瘤(SLL)。在至少两次系统治疗后复发或难治性滤泡性淋巴瘤(FL)。这一指示在基于总体响应率的加速批准下得到批准。继续批准这个指征可能是在确认试验中偶然验证和描述临床益处。

剂量与给药：口服25毫克，每日两次。

剂型和强度：胶囊，25毫克，15毫克。

禁忌症：无。

警告和注意事项：(1)肝毒性：监测肝功能。嗜中性白血球减少症：监测血液计数。(2)胚胎胎儿毒性：CopikTRA可引起胎儿损伤。向胎儿告知潜在的风险，并使用有效的避孕方法。

不良反应：最常见的不良反应(>20%)是腹泻或结肠炎、中性粒细胞减少、皮疹、疲劳、发热、咳嗽、恶心、上呼吸道感染、肺炎、肌肉骨骼疼痛和贫血。

药物相互作用：(1)CYP3A诱导剂：避免与强CYP3受体共同给药。(2)CYP3A抑制剂：当与强或中度CYP3A抑制剂联合使用时，监测CopiktA毒性。ReduceCOPIKTRA剂量为15毫克，每天两次，当与强大的CYP3A4抑制剂共同施用。(3)CYP3A底物：当CopikTa与敏感的CYP3A底物共同作用时，监测毒性的迹象。

特定人群中的使用：哺乳期，建议妇女不要母乳喂养。

储存：20°到25°C(68°到77°F)，允许旅游在15°到30°C(59°到86°F)。保留在原来的包装，直到配药。分配泡罩包装在原始容器中。

英文版说明书：

COPIKTRA(duvelisib)，capsules for oral useInitial U.S. Approval: 2018IMPORTANT SAFETY INFORMATION AND INDICATIONSIMPORTANT SAFETY INFORMATIONWARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS， DIARRHEA OR COLITIS， CUTANEOUS REACTIONS， and PNEUMONITISFatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.WARNINGS AND PRECAUTIONSInfections: Serious， including fatal (18/442; 4%)， infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N=442). The most common serious infections were pneumonia， sepsis， and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months)， with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. For grade 3 or higher infection， withhold COPIKTRA until infection is resolved. Resume COPIKTRA at the same or reduced dose. Serious， including fatal， Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA and following completion of treatment with COPIKTRA until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold COPIKTRA in patients with suspected PJP of any grade， and permanently discontinue if PJP is confirmed. Cytomegalovirus (CMV) reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia， withhold COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed， administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.Diarrhea or Colitis: Serious， including fatal (1/442; <1%)， diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months)， with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month). Advise patients to report any new or worsening diarrhea. For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e.， up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis， initiate supportive care with antidiarrheal agents， continue COPIKTRA at the current dose， and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy， withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g.， budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea， consider restarting COPIKTRA at a reduced dose. For patients presenting with abdominal pain， stool with mucus or blood， change in bowel habits， peritoneal signs， or with severe diarrhea (Grade 3) (i.e.， > 6 stools per day over baseline)， withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g.， budesonide) or systemic steroids. A diagnostic work-up to determine etiology， including colonoscopy， should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis， restart COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade， discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening diarrhea or colitis.Cutaneous Reactions: Serious， including fatal (2/442; <1%)， cutaneous reactions occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months， 75th percentile: 6 months) with a median event duration of 1 month (range: 1 day to 37 months， 75th percentile: 2 months). Presenting features for the serious events were primarily described as pruritic， erythematous， or maculo-papular. Less common presenting features include exanthem， desquamation， erythroderma， skin exfoliation， keratinocyte necrosis， and papular rash. Advise patients to report new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions， continue COPIKTRA at the current dose， initiate supportive care with emollients， antihistamines (for pruritus)， or topical steroids， and monitor the patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event， restart COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe cutaneous reaction does not improve， worsens， or recurs. For life-threatening cutaneous reactions， discontinue COPIKTRA. In patients with SJS， TEN， or DRESS of any grade， discontinue COPIKTRA.Pneumonitis: Serious， including fatal (1/442; <1%)， pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months)， with 75% of cases occurring within 9 months. The median event duration was 1 month， with 75% of cases resolving by 2 months. Withhold COPIKTRA in patients with new or progressive pulmonary signs and symptoms such as cough， dyspnea， hypoxia， interstitial infiltrates on a radiologic exam， or a decline by more than 5% in oxygen saturation， and eva luate for etiology. If the pneumonitis is infectious， patients may be restarted on COPIKTRA at the previous dose once the infection， pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2)， treat with systemic corticosteroids and resume COPIKTRA at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy， discontinue COPIKTRA. For severe or life-threatening non-infectious pneumonitis， discontinue COPIKTRA and treat with systemic steroids.Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%， respectively， of patients receiving COPIKTRA 25 mg BID (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months)， with a median event duration of 1 month (range: 1 day to 16 months). Monitor hepatic function during treatment with COPIKTRA. For Grade 2 ALT/AST elevation (> 3 to 5 X ULN)， maintain COPIKTRA dose and monitor at least weekly until return to < 3 X ULN. For Grade 3 ALT/AST elevation (> 5 to 20 X ULN)， withhold COPIKTRA and monitor at least weekly until return to < 3 X ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced dose for subsequent occurrences. For grade 4 ALT/AST elevation (> 20 X ULN)， discontinue COPIKTRA.Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA 25 mg BID (N=442)， with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months (range: 3 days to 31 months)， with 75% of cases occurring within 4 months. Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy， and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L， then resume COPIKTRA at same dose for the first occurrence or at a reduced dose for subsequent occurrences.Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action， COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.ADVERSE REACTIONSB-cell Malignancies SummaryFatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%)， diarrhea or colitis (18%)， pneumonia (17%)， rash (5%)， and pneumonitis (5%). Adverse reactions resulted in treatment discontinuation in 156 patients (35%) most often due to diarrhea or colitis， infection， and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions， most often due to diarrhea or colitis and transaminase elevation. The most common adverse reactions (reported in ≥20% of patients) were diarrhea or colitis， neutropenia， rash， fatigue， pyrexia， cough， nausea， upper respiratory infection， pneumonia， musculoskeletal pain and anemia.CLL/SLLFatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). COPIKTRA was discontinued in 57 patients (36%)， most often due to diarrhea or colitis， infection， and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions most often due to diarrhea or colitis and rash. The most common adverse reactions with COPIKTRA (reported in ≥20% of patients) were diarrhea or colitis， neutropenia， pyrexia， upper respiratory tract infection， pneumonia， rash， fatigue， nausea， anemia and cough.FLSerious adverse reactions were reported in 58% of patients and most often involved diarrhea or colitis， pneumonia， renal insufficiency， rash， and sepsis. The most common adverse reactions (≥20% of patients) were diarrhea or colitis， nausea， fatigue， musculoskeletal pain， rash， neutropenia， cough， anemia， pyrexia， headache， mucositis， abdominal pain， vomiting， transaminase elevation， and thrombocytopenia. Adverse reactions resulted in COPIKTRA discontinuation in 29% of patients， most often due to diarrhea or colitis and rash. COPIKTRA was dose reduced in 23% due to adverse reactions， most often due to transaminase elevation， diarrhea or colitis， lipase increased and infection.DRUG INTERACTIONSCYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

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英文版说明书：

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