HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab- Paclitaxel/Gemcitabine Versus Nab- Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma

被引：349

作者：

Hingorani, Sunil R. ^{[1
]}

Zheng, Lei ^{[3
]}

Bullock, Andrea J. ^{[4
]}

Seery, Tara E. ^{[5
]}

Harris, William P. ^{[2
]}

Sigal, Darren S. ^{[6
]}

Braiteh, Fadi ^{[10
]}

Ritch, Paul S. ^{[11
,12
]}

Zalupski, Mark M. ^{[13
]}

Bahary, Nathan ^{[14
]}

Oberstein, Paul E. ^{[15
]}

Wang-Gillam, Andrea ^{[16
]}

Wu, Wilson ^{[7
]}

Chondros, Dimitrios ^{[7
]}

Jiang, Ping ^{[7
]}

Khelifa, Sihem ^{[17
]}

Pu, Jie ^{[17
]}

Aldrich, Carrie ^{[17
]}

Hendifar, Andrew E. ^{[8
,9
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M5-C800, Seattle, WA 98109 USA

[2] Univ Washington, Sch Med, Seattle, WA USA

[3] Johns Hopkins Univ, Sch Med, Baltimore, MD USA

[4] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[5] Chan Soon Shiong Inst Med, El Segundo, CA USA

[6] Scripps Canc Ctr, La Jolla, CA USA

[7] Halozyme Therapeut, San Diego, CA USA

[8] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[9] Samuel Oschin Canc Ctr, Los Angeles, CA USA

[10] Comprehens Canc Ctr Nevada, Las Vegas, NV USA

[11] Froedtert Hosp, Milwaukee, WI USA

[12] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[13] Univ Michigan, Ann Arbor, MI 48109 USA

[14] Univ Pittsburgh, Med Ctr, Canc Pavil, Pittsburgh, PA USA

[15] Columbia Univ, Med Ctr, New York, NY USA

[16] Washington Univ, St Louis, MO USA

[17] Ventana Med Syst, Tucson, AZ USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2018年 / 36卷 / 04期

关键词：

VENOUS THROMBOEMBOLISM; CANCER; GEMCITABINE; PREVENTION; PRESSURE; GUIDANCE; SOLIDS; FLUIDS; TUMORS;

D O I：

10.1200/JCO.2017.74.9564

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining >= 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P =.049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P =.048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial. (C) 2017 by American Society of Clinical Oncology

引用

页码：359 / +

页数：12

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