1129TiPA PHASE 1B/2, MULTICENTER, OPEN LABEL TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF TALIMOGENE LAHERPAREPVEC (T-VEC) AND IPILIMUMAB (IPI) VERSUS IPI ALONE IN PREVIOUSLY UNTREATED, UNRESECTED, STAGE IIIB, IIIC, AND IV MELANOMA.
1129TiPA PHASE 1B/2, MULTICENTER, OPEN LABEL TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF TALIMOGENE LAHERPAREPVEC (T-VEC) AND IPILIMUMAB (IPI) VERSUS IPI ALONE IN PREVIOUSLY UNTREATED, UNRESECTED, STAGE IIIB, IIIC, AND IV MELANOMA.
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1129TiPA 1B/2 期、多中心、开放标签试验，评估 TALIMOGENE LAHERPAREPVEC (T-VEC) 和 IPILIMMAB (IPI) 与单独 IPI 在先前未经治疗、未切除的 IIIB、IIIC 和 IV 期黑色素瘤中的安全性和有效性。
DOI：
10.1093/annonc/mdu344.45
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
H. Kaufman
中科院分区：
文献类型：
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作者：
F. Collichio;M. Milhem;R. Andtbacka;I. Puzanov;Y. Saenger;J. Chesney;L. Cranmer;O. Hamid;T. Logan;J. Glaspy;C. Lebbé;C. Garbe;J. Gansert;A. Li;J. Chou;H. Kaufman
背景：T-VEC是一种基于单纯疱疹病毒1的溶瘤免疫疗法，旨在选择性地在癌细胞中复制并产生GM-CSF以启动全身抗肿瘤免疫反应。OPTiM是一项T-VEC vs GM-CSF治疗未切除的IIIB-IV期黑色素瘤的3期试验，其主要终点是T-VEC具有更高的持久缓解率。客观缓解率（ORR）为26.4% vs 5.7%，完全缓解率（CR）为10.8% vs 0.7%。免疫检查点阻断与ipi改善晚期黑色素瘤的总生存期（OS）。根据免疫相关反应标准（irRC）， Ipi的ORR为10-15%，CR为1-2%。一项1b/2期研究旨在评估T-VEC加入ipi作为启动方案的安全性和有效性（clinicaltrials.gov #NCT01740297）。第1b期试验表明，该组合是可以接受的，第2期试验于2013年8月开始。试验设计：第2期评估T-VEC + ipi与单独使用ipi在未经治疗、不可切除的IIIB-IV期黑色素瘤中的疗效和安全性。大约140名患者将按1:1的比例随机分配。主要终点是操作系统。次要终点：安全性、ORR、反应时间、反应持续时间、无进展生存期、切除率、1年和2年生存期。主要入选标准：首次接受全身治疗（辅助治疗除外）的IIIB-IV期不可切除黑色素瘤；ECOG性能状态0-1；可衡量的疾病;≥1个可注射皮下/皮下/淋巴结肿瘤；无脑转移；无症状性自身免疫；没有免疫抑制;没有艾滋病毒/乙肝病毒和丙肝病毒;没有抗疱疹治疗。T-VEC在第1周第1天注射到非内脏病变，注射量为4 × 106斑块形成单位/mL (pfu/mL)；d1至4 × 108 pfu/mL，第4周；然后q2w。从第6周开始，Ipi给药3mg /kg IV q3w × 4，同时给药3次T-VEC。T-VEC治疗持续到所有可注射肿瘤消失，按irRC标准疾病进展或不耐受。在美国开始招生，预计在2014年12月在法国/德国开放。结合T-VEC和ipi是一种新的免疫治疗方法，可以促进抗肿瘤免疫的启动，同时增强抗肿瘤t细胞反应。披露：F.A. Collichio：他曾担任安进公司（Amgen, Inc.）的顾问委员会成员，并收取顾问费。她获得了安进、诺华、葛兰素史克、Morphotec和百时美施贵宝的临床试验研究支持；M. Milhem：他曾参与Genentech和Amgen， Inc.的顾问委员会；R.H. Andtbacka: Andtbacka博士曾参与安进公司（Amgen, Inc.）顾问委员会；I. Puzanov：他曾因参与安进公司（Amgen, Inc.）顾问委员会而获得荣誉。他的机构从Amgen， Inc.获得研究经费；Y. senger：曾参与安进公司（Amgen, Inc.）的顾问委员会；J. Chesney：他曾担任Amgen， Inc.的顾问委员会成员。O. Hamid: Hamid博士曾担任Amgen， Inc.的顾问，并获得了Amgen， Inc.的临床试验支持；T. Logan: Dr. Logan所在的机构从Amgen， Inc.获得了赠款、写作协助、药品、设备或行政支持；J. Glaspy：他曾担任安进公司（Amgen, Inc.）的顾问并获得其研究支持；C. Lebbe: Lebbe博士曾参与Roche， GlaxoSmithKline, Novartis， Bristol-Myers Squibb和Amgen， Inc.的顾问委员会；J. Gansert：他是Amgen， Inc.的有偿员工和股东；a . Li: Li是Amgen， Inc.的有偿员工和股东；J. Chou: Chou博士是Amgen， Inc.的有偿员工和股东；H. Kaufman：他曾因参与顾问委员会而获得Amgen， Inc.的酬金，并因进行临床试验而获得Amgen， Inc.的研究经费。所有其他作者都声明没有利益冲突。
ABSTRACT Background: T-VEC is a herpes simplex virus-1 based oncolytic immunotherapy designed to selectively replicate in cancer cells and produce GM-CSF to initiate systemic antitumor immune responses. OPTiM, a phase 3 trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma, met its primary endpoint of higher durable response rate in favor of T-VEC. Objective response rate (ORR) was 26.4% vs 5.7%, with complete response (CR) 10.8% vs 0.7% in favor of T-VEC. Immune checkpoint blockade with ipi improves overall survival (OS) in advanced melanoma. Ipi has a 10-15% ORR with 1-2% CR by immune-related response criteria (irRC). A phase 1b/2 study was designed to evaluate safety and efficacy when T-VEC is added to ipi as a priming regimen (clinicaltrials.gov #NCT01740297). Phase 1b showed the combination was tolerable, and phase 2 opened in Aug 2013. Trial design: Phase 2 evaluates the efficacy and safety of T-VEC + ipi vs ipi alone in untreated, unresectable stage IIIB-IV melanoma. Approximately 140 patients will be randomized 1:1. The primary endpoint is OS. Secondary endpoints: safety, ORR, time to response, duration of response, progression-free survival, resection rate, 1- and 2-yr survival. Key eligibility criteria: unresectable stage IIIB-IV melanoma naive to systemic therapy (except adjuvant); ECOG performance status 0-1; measurable disease; ≥1 injectable cutaneous/ subcutaneous/ nodal tumor; no brain metastases; no symptomatic autoimmunity; no immunosuppression; no HIV/HBV/HCV; no antiherpetic therapy. T-VEC is injected into nonvisceral lesions up to 4 × 106 plaque forming units/mL (pfu/mL) on d1, wk 1; up to 4 × 108 pfu/mL d1, wk 4; then q2w. Ipi is dosed 3 mg/kg IV q3w × 4 starting wk 6 with the 3rd T-VEC dose. Treatment with T-VEC continues until all injectable tumors have disappeared, disease progression per irRC, or intolerance. Enrollment began in the USA and is expected to open in France/Germany by Dec 2014. Combining T-VEC and ipi represents a novel immunotherapeutic approach to promote the initiation of antitumor immunity and simultaneously enhance antitumor T-cell responses. Disclosure: F.A. Collichio: Dr. Collichio has served on an advisory board and received consultant fees from Amgen, Inc. She receives clinical trial research support from Amgen, Novartis, GlaxoSmithKline, Morphotec, and Bristol-Myers Squibb; M. Milhem: Dr. Milhem has participated on advisory boards for Genentech and Amgen, Inc.; R.H. Andtbacka: Dr. Andtbacka has participated in advisory boards for Amgen, Inc.; I. Puzanov: Dr. Puzanov has received honoraria for participation on advisory boards for Amgen, Inc. His institution receives research funding from Amgen, Inc.; Y. Saenger: Dr. Saenger has participated in advisory boards for Amgen, Inc.; J. Chesney: Dr. Chesney has served on an advisory board for Amgen, Inc. O. Hamid: Dr. Hamid has served as a consultant for Amgen, Inc. and has received clinical trials support from Amgen, Inc.; T. Logan: Dr. Logan's institution has received grant money, and writing assistance, medicines, equipment, or administrative support from Amgen, Inc.; J. Glaspy: Dr. Glaspy has served as a consultant to and received research support from Amgen, Inc.; C. Lebbe: Dr. Lebbe has participated in advisory boards for Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Amgen, Inc.; J. Gansert: Dr. Gansert is a compensated employee and stockholder of Amgen, Inc.; A. Li: Ai Li is a compensated employee and stockholder of Amgen, Inc.; J. Chou: Dr. Chou is a compensated employee and stockholder of Amgen, Inc.; H. Kaufman: Dr. Kaufman has received honoraria from Amgen, Inc. for participation in advisory boards and has received research funding from Amgen, Inc. for conducting clinical trials. All other authors have declared no conflicts of interest.