海报库PosterKeep
PO.CT01.05 · 临床试验

VIRAGE试验中肿瘤和生物标志物应答的分析：一项随机、IIb期、开放标签研究，评估nab-紫杉醇和吉西他滨联合或不联合静脉注射VCN-01治疗转移性胰腺癌（mPDAC）患者

Analysis of tumor and biomarker responses in the VIRAGE Trial, a randomized Phase IIb, open-label, study of nab-paclitaxel and gemcitabine with/without intravenous VCN-01 in patients with metastatic pancreatic cancer (mPDAC)

海报缩略图：VIRAGE试验中肿瘤和生物标志物应答的分析：一项随机、IIb期、开放标签研究，评估nab-紫杉醇和吉西他滨联合或不联合静脉注射VCN-01治疗转移性胰腺癌（mPDAC）患者
编号 CT162 展板 26 时间 4/20 02:00–05:00 区域 Section 52 主讲 Manuel Hidalgo, MD;PhD
分会场 Phase II and Phase III Clinical Trials
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作者与单位 Authors & Affiliations

Rocio Garcia-Carbonero1, Roberto Pazo2, Teresa Macarulla3, Berta Laquente4, Alana Nguyen5, Carmen Guillén-Ponce6, Andres J. Muñoz7, Edward J. Kim8, Mireya Cazorla9, Tara Seery10, Miriam Lobo de Mena11, Chris Nevala-Plagemann12, Vivek R. Sharma13, Eva Martinez de Castro14, Charles Le15, Ana Mato-Berciano16, Luis A. Rojas16, Carmen Blasco16, Manel Cascallo16, Manuel Hidalgo17

1Hospital Universitario Doce de Octubre, Imas 12, Madrid, Spain,2Hospital Universitario Miguel Servet, Zaragoza, Spain,3Hospital Universitari Vall d’Hebron, Barcelona, Spain,4Catalan Institute of Oncologia, Barcelona, Spain,5Weill Cornell Medicine/NYP Hospital, New York, NY,6Hospital Universitario Ramón y Cajal, Madrid, Spain,7Hospital Universitario Gregorio Marañón, Madrid, Spain,8UC Davis Comprehensive Cancer Center, Sacramento, CA,9Hospital Regional Universitario, Malaga, Spain,10Hoag Memorial Hospital Presbyterian, Newport Beach, CA,11Consorcio Hospital General Universitario de Valencia, Valencia, Spain,12Huntsman Cancer Institute, University of Utah, Salt Lake City, UT,13University of Louisville, Louisville, KY,14Hospital Universitario Marqués de Valdecilla, Santander, Spain,15Theriva Biologics Inc, Rockville, MD,16Theriva Biologics SL, Parets del Valles, Spain,17NYU Langone Health Perlmutter Cancer Ctr., New York, NY

摘要 Abstract

中文摘要
背景：VCN-01（zabilugene almadenorepvec）是一种表达透明质酸酶的溶瘤腺病毒，可降解肿瘤基质、促进化疗药物渗透并刺激肿瘤免疫，正在针对不同癌症适应证进行开发。这项随机、开放标签、IIb期VIRAGE试验测试了2剂静脉注射（IV）VCN-01联合标准治疗（SoC）吉西他滨/nab-紫杉醇（GA）治疗mPDAC的疗效和安全性。 方法：未接受过化疗的mPDAC患者按1:1随机分组，在重复的28天周期的第1、8和15天接受SoC剂量的GA（I组），或在GA第1和第4周期前1周接受2次单独的IV剂量VCN-01（1x10^13 vp/剂）（II组）。主要终点为总生存期（OS）和安全性。次要目标包括无进展生存期（PFS）、客观缓解率（ORR）、缓解持续时间（DoR）和Ca19.9变化。同时分析了血液中的VCN-01基因组和血清中中和性抗腺病毒抗体（anti-Ad-NAb）水平。 结果：试验中96名患者至少接受了1剂GA或VCN-01+GA（每组48名患者）。II组和I组的中位OS分别为10.8对8.6个月（HR 0.57，95% CI 0.34-0.96；P=0.055），PFS为7.0对4.6个月（HR 0.55，95% CI 0.34-0.88；P=0.011）。VCN-01+GA相较于单用GA的OS获益在不同亚组中保持一致，包括年龄超过70岁、存在肝转移或转移部位>2处的患者。与I组中开始GA第4周期的患者相比，II组中接受2剂VCN-01并开始GA第4周期的患者显示出更大的OS改善（14.8对11.6个月；HR 0.44；95% CI 0.21-0.92；P=0.046）和PFS改善（11.2对7.4个月；HR 0.48；95% CI 0.25-0.91；P=0.017）。ORR为39.6%对31.3%（P=0.314），VCN-01+GA组比GA组有更多患者出现靶肿瘤缩小（84.1%对69.8%；P=0.13）。VCN-01+GA的DoR更长（11.2对5.4个月；HR 0.22；95% CI 0.08-0.62；P=0.004），且该组19名患者中有8名在第二剂VCN-01后（随机化后>4个月）达到迟发性客观缓解。II组的Ca19.9水平下降更为显著，至第3周期时I组对II组的中位降幅为-61.0%对-64.9%，至第9周期时（第二剂VCN-01后）进一步下降至-16.7%对-86.3%。未观察到anti-Ad-NAb基线水平与OS或PFS之间的相关性。血液中病毒基因组水平的峰值在第一剂和第二剂VCN-01之间相似。 结论：与I组（GA）患者相比，II组（VCN-01+GA）mPDAC患者显示出改善的OS和PFS以及更迟发和更持久的缓解。与接受等量周期GA的患者相比，接受第二剂VCN-01+GA的患者显示出进一步延迟的疾病进展和延长的患者生存期。
查看英文原文 English abstract
Background: VCN-01 (zabilugene almadenorepvec) is an oncolytic adenovirus expressing hyaluronidase to degrade tumor stroma, facilitate chemotherapy penetration and stimulate tumor immunity, which is being developed for different cancer indications. The randomized, open-label, Phase 2b VIRAGE trial tested the efficacy and safety of 2 intravenous (IV) doses of VCN-01 combined with standard of care (SoC) gemcitabine/nab-paclitaxel (GA) in mPDAC. Methods: Chemonaïve mPDAC patients were randomized 1:1 to receive SoC doses of GA on days 1, 8 and 15 of repeated 28-day cycles (Arm I) or 2 separate IV doses of VCN-01 (1x10 13 vp/dose) 1 week prior to cycles 1 and 4 of GA (Arm II). Primary endpoints were overall survival (OS) and safety. Secondary objectives included progression free survival (PFS), objective response rates (ORR), duration of response (DoR) and Ca19.9 changes. VCN-01 genomes in blood and serum levels of neutralizing anti-adenovirus antibodies (anti-Ad-NAb's) were also analyzed. Results: 96 patients in the trial received at least 1 dose of GA or VCN-01+GA (48 patients in each arm). Median OS was 10.8 vs. 8.6 months for Arm II and Arm I, respectively (HR 0.57, 95% CI 0.34-0.96; P =0.055) and PFS was 7.0 vs. 4.6 months (HR 0.55, 95% CI 0.34-0.88; P =0.011). OS benefits with VCN-01+GA vs. GA alone were consistent across different subgroups, including patients aged over 70 years, presence of hepatic metastases, or patients with >2 metastatic sites. Compared to patients in Arm I who started cycle 4 of GA, patients in Arm II who received 2 VCN-01 doses and started cycle 4 of GA showed greater improvement in OS (14.8 vs 11.6 months; HR 0.44; 95% CI 0.21-0.92; P =0.046) and PFS (11.2 vs 7.4 months; HR 0.48; 95% CI 0.25-0.91; P =0.017). ORR was 39.6% vs. 31.3% ( P =0.314), and more patients had target tumor shrinkage with VCN-01 + GA than GA (84.1% vs. 69.8%; P =0.13). DoR was longer for VCN-01+GA (11.2 vs 5.4 months; HR 0.22; 95% CI 0.08 - 0.62; P =0.004) and 8 of 19 patients in this group achieved late objective responses after the second VCN-01 dose (>4 months after randomization). Ca19.9 levels declined more markedly in Arm II, with a median reduction of -61.0% versus -64.9% in Arm I vs. Arm II by cycle 3, and a further decrease to -16.7% vs -86.3% by cycle 9, following the second VCN-01 dose. No correlation between baseline levels of anti-Ad-NAbs and OS or PFS were observed. The peak of viral genome levels in blood was similar between the first and the second dose of VCN-01. Conclusions: Compared to patients in Arm I (GA), mPDAC patients in Arm II (VCN-01+GA) showed improved OS and PFS and later and more durable responses. Patients that received a second VCN-01 dose+GA showed a further delayed disease progression and extended patient survival compared to patients that received equivalent cycles of GA.
利益披露 Disclosure
R. Garcia-Carbonero, Astellas Other, Advisory Board. Ipsen Other, Advisory Board. MSD ). Pfizer ). R. Pazo, Astellas ), Other, Invited Speaker, Advisory Board. Astra Zeneca Other, Expert Testimony, Advisory Board. BMS Other, Invited Speaker, Advisory Board. Eisai Other, Invited Speaker. Ipsen ), Other, Advisory Board. Lilly Other, Expert Testimony. Roche Other, Invited Speaker, Advisory Board. Servier Other, Invited Speaker, Advisory Board. T. Macarulla, Amgen Other, Consultant or Advisory Role. Servier Other, Consultant or Advisory Role, Invited Speaker. Incyte ), Other, Consultant or Advisory Role, Invited Speaker. Sanofi Other, Consultant or Advisory Role. Astra Zeneca ), Other, Consultant or Advisory Role, Invited Speaker. Taiho Other, Consultant or Advisory Role. Celgene ), Other, Consultant or Advisory Role. Eisai Other, Consultant or Advisory Role, Invited Speaker. BeiGene ). Roche Other, Invited Speaker. B. Laquente, Jazz Pharmaceuticals Other, Advisory Board. Astellas ), Other, Advisory Board. Taiho ). Astra Zeneca ). Theriva Biologics ). A. Nguyen, ReMission ). C. Guillén-Ponce, BeOne ). Incyte ). PH Research ). Novartis ). Erytech Pharma ). Halozyme ). Theriva Biologics ). A. J. Muñoz, Leo Pharma ), Other, Advisory Services. Sanofi ), Other, Advisory Services. BMS ), Other, Advisory Services. Celgene ), Other, Advisory Services. GSK Other, Advisory Services. Pfizer Other, Advisory Services. Astra Zeneca Other, Advisory Services. MSD Other, Advisory Services. Lilly Other, Advisory Services. Servier Other, Advisory Services. Roche Other, Advisory Services. Taiho Other, Advisory Services. Regeneron Other, Advisory Services. Rovi Other, Advisory Services. Menarini Other, Advisory Services. Stada Other, Advisory Services. Medscape Other, Advisory Services. E. J. Kim, Relay Therapeutics Other, Advisory Role. Eisai Other, Speakers' Bureau. Pfizer Other, Speakers' Bureau. Merck ). EpicentRx ). Astellas ). Erytech ). Fibrogen ). NGM BIOPHARMACEUTICALS ). Eureka Therapeutics ). Genentech ). GlaxoSmithKline ). M. Cazorla, None. T. Seery, Astellas Other, Advisory Board. Revolution Medicines Other, Advisory Board. M. Lobo de Mena, Astra Zeneca Other, Invited speaker. Incyte Other, Invited speaker. Leo Pharma Other, Invited speaker. Novartis Other, Invited speaker. Servier Other, Invited speaker. C. Nevala-Plagemann, Seagene Other, Advisory Role. V. R. Sharma, Sanofi Other, Invited Speaker. Alexion Other, Invited Speaker. Astra Zeneca Other, Invited Speaker. E. Martinez de Castro, None. C. Le, Theriva Biologics Employment, Stock Option. A. Mato-Berciano, Theriva Biologics Employment, Stock, Stock Option. L. A. Rojas, Theriva Biologics Employment, Stock Option. C. Blasco, Theriva Biologics Employment, Stock, Stock Option. M. Cascallo, Theriva Biologics Employment, Stock, Stock Option, Patent. M. Hidalgo, Champions Oncology Stock, Other, Advisory Board. InxMed Stock, Other, Advisory Board. Oncomatrix Other Business Ownership, Other, Advisory Board. Peaches Other, Advisory Board. Thetis Other, Advisory Board. Velavigo Stock, Other, Advisory Board. BMS g., Board of Directors, non-salaried role), Stock. Guardant Health g., Board of Directors, non-salaried role), Stock. Nelum Pharmaceuticals Other Business Ownership. Incyte ). Theriva Biologics ).

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