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Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2019-09-20 , DOI: 10.1158/1078-0432.ccr-18-3965 David E Gerber 1 , Jeffrey R Infante 2 , Michael S Gordon 3 , Sarah B Goldberg 4 , Miguel Martín 5 , Enriqueta Felip 6 , Maria Martinez Garcia 7 , Joan H Schiller 8 , David R Spigel 9 , Julie Cordova 10 , Valerie Westcott 10 , Yulei Wang 10 , David S Shames 10 , YounJeong Choi 10 , Robert Kahn 10 , Randall C Dere 10 , Divya Samineni 10 , Jian Xu 10 , Kedan Lin 10 , Katie Wood 10 , Stephanie Royer-Joo 10 , Vanessa Lemahieu 10 , Eva Schuth 10 , Anjali Vaze 10 , Daniel Maslyar 10 , Eric W Humke 10 , Howard A Burris 9
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2019-09-20 , DOI: 10.1158/1078-0432.ccr-18-3965 David E Gerber 1 , Jeffrey R Infante 2 , Michael S Gordon 3 , Sarah B Goldberg 4 , Miguel Martín 5 , Enriqueta Felip 6 , Maria Martinez Garcia 7 , Joan H Schiller 8 , David R Spigel 9 , Julie Cordova 10 , Valerie Westcott 10 , Yulei Wang 10 , David S Shames 10 , YounJeong Choi 10 , Robert Kahn 10 , Randall C Dere 10 , Divya Samineni 10 , Jian Xu 10 , Kedan Lin 10 , Katie Wood 10 , Stephanie Royer-Joo 10 , Vanessa Lemahieu 10 , Eva Schuth 10 , Anjali Vaze 10 , Daniel Maslyar 10 , Eric W Humke 10 , Howard A Burris 9
Affiliation
PURPOSE
This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E).
PATIENTS AND METHODS
LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D).
RESULTS
Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline).
CONCLUSIONS
LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
中文翻译：
非小细胞肺癌和铂耐药性卵巢癌患者抗NaPi2b抗体-药物结合物Lifastuzumab Vedotin DNIB0600A的Ia期研究。
目的该I期试验评估了利法妥珠单抗vedotin（LIFA），抗NaPi2b mAb的抗体-药物偶联物（MNIB2126A）和有效的抗有丝分裂剂（单甲基澳瑞他汀E）的安全性，耐受性和初步的抗肿瘤活性。患者和方法LIFA通过静脉内输注每3周一次施用于患有非小细胞肺癌（NSCLC）和铂耐药性卵巢癌（PROC）的患者。在这种3 + 3剂量递增设计中，起始剂量为0.2 mg / kg，然后以推荐的II期剂量（RP2D）进行队列扩展。结果总体上，有87例患者接受了0.2至2.8 mg / kg的剂量治疗。未达到MTD；基于总体耐受性概况，每3周选择一次2.4 mg / kg作为RP2D。无论与研究药物有何种关系，任何级别的最常见不良事件都是疲劳（59％），恶心（49％），食欲下降（37％），呕吐（32％）和周围感觉神经病（29％）。在接受RP2D治疗的患者中，最常见的与治疗相关的≥3级毒性（n = 63）为中性粒细胞减少症（10％），贫血（3％）和肺炎（3％）。药代动力学曲线与剂量成正比。在活性剂量≥1.8mg / kg时，根据RECIST，在51例NSCLC患者中有4例（8％）和24例PROC患者中有11例（46％）观察到部分缓解。通过IHC，所有RECIST反应均发生在NaPi2b高的患者中。对≥1.8mg / kg的PROC患者进行的CA-125生物标志物评估显示，24人中有13人（54％）有反应（比基线下降≥50％）。结论LIFA表现出与剂量成比例的药代动力学，并且具有可接受的安全性，
更新日期：2020-01-16
中文翻译：
非小细胞肺癌和铂耐药性卵巢癌患者抗NaPi2b抗体-药物结合物Lifastuzumab Vedotin DNIB0600A的Ia期研究。
目的该I期试验评估了利法妥珠单抗vedotin（LIFA），抗NaPi2b mAb的抗体-药物偶联物（MNIB2126A）和有效的抗有丝分裂剂（单甲基澳瑞他汀E）的安全性，耐受性和初步的抗肿瘤活性。患者和方法LIFA通过静脉内输注每3周一次施用于患有非小细胞肺癌（NSCLC）和铂耐药性卵巢癌（PROC）的患者。在这种3 + 3剂量递增设计中，起始剂量为0.2 mg / kg，然后以推荐的II期剂量（RP2D）进行队列扩展。结果总体上，有87例患者接受了0.2至2.8 mg / kg的剂量治疗。未达到MTD；基于总体耐受性概况，每3周选择一次2.4 mg / kg作为RP2D。无论与研究药物有何种关系，任何级别的最常见不良事件都是疲劳（59％），恶心（49％），食欲下降（37％），呕吐（32％）和周围感觉神经病（29％）。在接受RP2D治疗的患者中，最常见的与治疗相关的≥3级毒性（n = 63）为中性粒细胞减少症（10％），贫血（3％）和肺炎（3％）。药代动力学曲线与剂量成正比。在活性剂量≥1.8mg / kg时，根据RECIST，在51例NSCLC患者中有4例（8％）和24例PROC患者中有11例（46％）观察到部分缓解。通过IHC，所有RECIST反应均发生在NaPi2b高的患者中。对≥1.8mg / kg的PROC患者进行的CA-125生物标志物评估显示，24人中有13人（54％）有反应（比基线下降≥50％）。结论LIFA表现出与剂量成比例的药代动力学，并且具有可接受的安全性，
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