Zydelig(Idelalisib Tablets)-中文药名：艾代拉里斯片获欧盟批准用于治疗两种血液肿瘤 2014年9月19日，吉利德科学抗血癌新药获欧盟批准Zydelig(idelalisib)用于慢性淋巴细胞性白血病(CLL)和滤泡性淋巴瘤(FL)。具体地讲，这款PI3K-delta抑制剂被批准与罗氏美罗华（利妥昔单抗）合并用于治疗之前至少接受过一种治疗的CLL患者，或作为一线治疗药物用于因17p缺失或TP53基因突变而被认为不适合化疗的患者。对于FL适应症，Zydelig被许可作为单药用于对两种之前治疗耐药的患者。 吉利德科学表示，这次的批准在很大程度上基于Zydelig+美罗华3期研究116的数据，该研究的受试者为220名不能耐受标准化疗的复发性CLL患者。该试验在一个独立数据监察委员会确定Zydelig与美罗华单独治疗相比可明显延长无进展生存期后，于去年10月份提交终止。 此外，获批用于治疗FL是基于中期研究101-09的数据，该研究是在125名对美罗华及含有一种烷化剂的化疗药物耐药的无痛性非霍奇金淋巴瘤患者身上将Zydelig作为单药治疗进行测试。结果显示，在研究的72名FL患者身上，Zydelig达到了54%的总有效率，该公司表示称。 欧盟在此次批准之前，欧洲药品管理局人用医药产品委员会于7月份对Zydelig及强生的BTK抑制剂Imbruvica (ibrutinib)发布的积极的意见。当时，该机构指出，两款药物为B细胞恶性肿瘤患者提供了治疗选择，“因为它们的作用机制不同于以往获得许可的治疗药物。” 今年初，Zydelig在美国被批准与美罗华合并用于复发性CLL患者，及作为单药用于复发性FL或之前已至少接受过两种系统治疗的复发性小淋巴细胞淋巴瘤患者。 美国上市包装 欧洲上市包装： Zydelig (idelalisib) 100mg（http://www.medicines.org.uk/emc/medicine/29202） Zydelig (idelalisib) 150mg（http://www.medicines.org.uk/emc/medicine/29201） IMPORTANT SAFETY INFORMATION WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation Contraindications History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly. Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions Most common adverse reactions (incidence ≥20%; all grades) in clinical studies, when used alone or in combination with rituximab, were diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%); SAR were reported in 49% of patients and 10% of patients discontinued due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions Most common lab abnormalities (incidence ≥30%; all grades) in clinical studies were neutropenia, hypertriglyceridemia, hyperglycemia, and ALT/AST elevations Drug Interactions CYP3A inducers: Avoid coadministration with strong CYP3A inducers CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued INDICATIONS ZYDELIG is indicated for the treatment of Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies Relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies The FL and SLL indications were granted accelerated approval based on overall response rate; improvement in patient survival or disease-related symptoms has not been established -------------------------------------- New Drugs Online Report for idelalisib Information Generic Name: idelalisib   Trade Name: Zydelig  Synonym: GS-1101, GS1101, GS 1101, CAL-101  Entry Type: New molecular entity   Development and Regulatory status UK: Launched  EU: Launched  US: Launched  UK launch Plans: Available only to registered users Actual UK launch date: September 2014  Comments Zydelig was launched in the US in Jul 14 [16]. 29/09/2014 13:05:49  Sep 14: Launched in the UK [15]. 29/09/2014 12:37:53  Sept 14: Approved in EU. [14] 22/09/2014 11:55:47  Jul 14: The approved EU indication is use in combination with rituximab for treatment of adult patients with CLL who have received at least one prior therapy, or as first line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy [13]. 25/07/2014 13:13:34  Jul 14: EU positive opinion for idelalisib to treat patients with CLL and refractory follicular lymphoma [13]. 25/07/2014 13:10:29  July 14: Approved by US FDA for relapsed CLL in combination with rituximab. [12] 24/07/2014 09:52:38  Dec 13: Filed in the US [11]. 04/07/2014 14:40:42  Dec 13: FDA grants idelalisib Breakthrough Therapy designation for relapsed patients with CLL in the US [9]. 27/12/2013 09:33:42  Nov 13: Filing in the EU for the treatment of iNHL and CLL was validated by the EMA on November 20. It has been accepted for accelerated assessment and could be available for marketing in the EU in 2H 2014 [8].  10/12/2013 09:12:20  May 13: Gilead is in discussion with the FDA about possibly speeding approval of idelalisib for CLL [5] 17/05/2013 11:51:45  May 12: PIII study (Study 116) started [1]. 16/05/2012 17:23:39  Trial or other data Jan 14: Study 116 (NCT01539512 ) published in NEJM. The median PFS was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab [10]. 24/01/2014 11:22:28 Nov 13: Results from a PIII study (Study 116) evaluating idelalisib plus rituximab in patients with previously-treated CLL who were not fit for chemotherapy will be reported at ASH. The study was stopped early based on a pre-specified interim analysis. The study showed a 93% progression-free survival rate at 24 weeks, roughly double the results for rituximab alone, and the overall response rate was 81% (vs 13% with rituximab alone) [7]. 19/11/2013 18:24:40 Oct 13: PIII trial stopped early after interim analysis by an independent data monitoring committee found highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab vs. rituximab alone [6]. 10/10/2013 11:48:52 May 13: Positive data from a small PI study reported at ASCO. Of 54 patients whose cancer had relapsed after a median of 5 treatments, idelalisib + rituximab resulted in a rapid and durable shrinkage of tumours in more than half. Median PSF was 17 months. [5]. 17/05/2013 08:48:34 Aug 12: NCT01659021is a PIII randomized, controlled open-label study evaluating the efficacy and safety of GS-1101 (CAL-101) in combination with ofatumumab in 210 patients with previously treated chronic lymphocytic leukaemia. The primary outcome is progression free survival. The regimen will be: GS-1101 (oral; 150mg twice daily) + ofatumumab (IV; 300 mg on Day 1, then 1000 mg weekly until Week 24). In the comparator arm, patients will receive ofatumumab (IV; 300 mg on Day 1, then 2000 mg weekly until Week 24). Subjects who are tolerating ofatumumab in the comparator arm but experience progression of CLL are eligible to receive GS-1101 monotherapy in the extension study, GS-US-312-0120. The study starts Sep 12 and is due to complete Dec 15 (collection of primary outcome data Sep 14) [3]. 10/08/2012 11:06:36 NCT01569295 is a PIII, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of GS-1101 (150mg twice daily) in combination with bendamustine and rituximab for 390 patients with previously treated CLL. The primary outcome is progression free survival. The study stared in May 12 and is due to complete Dec 16 (date for primary data collection Oct 15) [3].  10/08/2012 11:06:16 NCT01539291 (GS-US-312-0117) is a PIII double-blind extension study of two different doses of single-agent GS 1101 (150 and 300mg twice daily, for 160 patients with previously treated CLL. Eligible subjects for enrolment will be from GS-US-312-0116 who are tolerating primary study therapy but experience CLL progression. The primary outcome is overall response rate. The study started in Mar 12 and is due to complete Mar 16 [3]. 10/08/2012 11:06:04 NCT01539512 (Study 116) started Feb 12 and is due to complete Dec 15 (with collection of primary data by Feb 14). Enrolled patients have received previous treatment for CLL. NCT01539291 (Study 117) started in Mar 12, and will enrol compliant subjects from 116 who are tolerating primary study therapy but experience CLL progression; they will receive GS-1101 monotherapy [2]. 01/06/2012 14:08:33 May 12: In the PIII Study 116, 160 patients in the US and Europe will be randomized to 8 infusions of rituximab over 24 weeks plus GS-1101 or placebo taken orally twice daily. The primary endpoint is progression-free survival. An extension trial, Study 117, will follow patients who tolerated primary study therapy. Gilead is also planning two further PIII studies starting in 2H 2012, Study 115, evaluating GS-1101 with bendamustine and rituximab for 24 weeks of therapy and a study of GS-1101 + ofatumumab [1].  16/05/2012 17:25:53 Evidence Based Evaluations EPAR  http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003843/WC500175379.pdf  NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/idelalisib-and-ofatumumab-for-relapsed-chronic-lym/  NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/idelalisib-with-rituximab-for-chronic-lymphocytic/  References   Available only to registered users  Category BNF Category: Drugs affecting the immune response (08.02) Pharmacology: Phosphatidylinositol 3-kinase delta (PI3K-delta) inhibitor   Epidemiology: CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000 a year. The incidence increases to more than 30 per 100,000 a year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years [4].   Indication: Chronic lymphocytic leukaemia (CLL)  Additional Details: relapsed (in combination with rituximab), or first-line in the presence of 17p deletion or TP53 mutation in pts unsuitable for chemo-immunotherapy  Method(s) of Administration   Oral  Company Information Name: Gilead Sciences  US Name: Gilead Sciences  Further Information Anticipated commissioning route (England) NHSE  High cost drug list? Awaiting Update Tariff Chemotherapy is locally negotiated. In NICE timetable: Yes  When: Oct / 2015  Note: www.nice.org.uk/guidance/indevelopment/gid-tag488  Implications Available only to registered users