Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer.
Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer.
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DOI：
10.1158/1078-0432.ccr-15-2010
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发表时间：
2016-06-15
期刊：
影响因子：
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通讯作者：
Devoe CE
中科院分区：
文献类型：
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作者：
Hingorani SR;Harris WP;Beck JT;Berdov BA;Wagner SA;Pshevlotsky EM;Tjulandin SA;Gladkov OA;Holcombe RF;Korn R;Raghunand N;Dychter S;Jiang P;Shepard HM;Devoe CE
这项 Ib 期研究评估了聚乙二醇化人重组透明质酸酶 (PEGPH20) 与吉西他滨 (Gem) 联合使用的安全性和耐受性，并确定了针对未经治疗的 IV 期转移性胰腺导管腺癌 (PDA) 患者的 II 期剂量。还评估了使用生物标志物和成像测量的客观缓解率和治疗效果。患者使用标准 3+3 剂量递增设计接受逐步增加的 PEGPH20 静脉注射剂量与 Gem 的联合治疗。在第1周期（8周）中，PEGPH20每周给药两次，持续4周，然后每周给药一次，持续3周； Gem 每周给药一次，持续 7 周，然后停药 1 周。在随后的每个 4 周周期中，每周施用一次 PEGPH20 和 Gem，持续 3 周，然后休息 1 周。在 PEGPH20 给药前后给予地塞米松 (8 mg)。评估了几个安全参数。 28 名患者入组并分别接受 1.0 (n = 4)、1.6 (n = 4) 或 3.0 μg/kg (n = 20) 的 PEGPH20。最常见的 PEGPH20 相关不良事件是肌肉骨骼和四肢疼痛、外周水肿和疲劳。血栓栓塞事件的发生率为29%。中位无进展生存期 (PFS) 和总生存期 (OS) 分别为 5.0 个月和 6.6 个月。在评估治疗前组织透明质酸 (HA) 水平的 17 名患者中，“高”HA 患者 (n = 6) 的中位 PFS 和 OS 率分别为 7.2 和 13.0 个月，“低”HA 患者 (n = 11) 的中位 PFS 和 OS 率分别为 3.5 和 5.7 个月。 PEGPH20 与 Gem 联合使用具有良好的耐受性，并且可能对晚期 PDA 患者（尤其是高 HA 肿瘤患者）具有治疗益处。
This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated. Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated. Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for “high”-HA patients (n = 6), and 3.5 and 5.7 months for “low”-HA patients (n = 11), respectively. PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors.