Final analysis of stage 1 data from a randomized phase II study of PEGPH20 plus nab-Paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients (pts), utilizing Ventana companion diagnostic assay.

Bullock, Andrea J.; Hingorani, Sunil R.; Wu, Xiaojie; Jiang, Ping; Chondros, Demetrios; Khelifa, Sihem; Aldrich, Carrie; Pu, Jie; Hendifar, Andrew Eugene

doi:10.1200/jco.2016.34.15_suppl.4104

Cited by 10 publications

(8 citation statements)

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“…the 50% HA level from the range of HA levels found in study patients' tumors). 37 In this respect this study was novel in identifying a biomarker with the potential …”

Section: Pegph20-a New Therapeutic Approach To the Treatment Of Pancrmentioning

confidence: 98%

“…Multiple preclinical and clinical studies have demonstrated that targeting the biophysical barrier to drug delivery in PDA with PEGPH20 is both feasible and promising. 12,25,34,37 Results from both the phase Ib 34 and phase II (HALO-202) 38 clinical trials have demonstrated that the administration of PEGPH20 with different cytotoxic chemotherapy combinations is feasible and effective.…”

Section: Perspective and Future Directionsmentioning

confidence: 99%

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Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Hendifar¹,

Bullock²

2017

Oncology &Amp; Hematology Review (US)

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N ew therapeutic approaches are urgently needed to improve survival for patients with metastatic pancreatic ductal adenocarcinoma (PDA). This carcinoma is characterized by a hyaluronan (HA)-rich desmoplastic stroma that raises tumor interstitial fluid pressure (IFP), which in turn compresses the vasculature and impedes access of anti-cancer therapies and immune cells to tumor sites. It is this biophysical barrier that is the target for PEGylated recombinant human hyaluronidase (PEGPH20; pegvorhyaluronidase alfa), which degrades HA polymers to tetra-and hexa-saccharides to remodel the tumor stroma. In preclinical models, PEGPH20 reduced IFP, and expanded tumor vasculature to improve perfusion, which increased access for innate immune cells, antibodies and therapeutic agents. The results of a phase Ib study have suggested benefits in overall survival and progression-free survival (PFS) for patients with tumors that accumulate HA (termed HA-High) treated with a combination of gemcitabine and PEGPH20. A phase II study demonstrated that HA could be a potential biomarker for identifying patients who may be most suitable for PEGPH20 treatment. HALO 109-202 showed positive outcomes for PFS especially in HA-High patients treated with PEGPH20 plus nab-paclitaxel and gemcitabine. A randomized, double-blind, phase III study exploring the benefits of PEGPH20 in HA-High patients with PDA is ongoing. Other PEGPH20-based combinations are being investigated in multiple stroma-rich cancers, including lung, gastric, and breast. PEGPH20 is the most advanced therapy targeting the tumor stroma and has the potential to form the therapeutic backbone for the treatment of stroma-rich tumors. KeywordsPancreatic ductal adenocarcinoma (PDA), tumor microenvironment (TME), hyaluronan (HA), PEGylated recombinant human hyaluronidase (PEGPH20)

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“…the 50% HA level from the range of HA levels found in study patients' tumors). 37 In this respect this study was novel in identifying a biomarker with the potential …”

Section: Pegph20-a New Therapeutic Approach To the Treatment Of Pancrmentioning

confidence: 98%

Section: Perspective and Future Directionsmentioning

confidence: 99%

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Hendifar¹,

Bullock²

2017

Oncology &Amp; Hematology Review (US)

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“…Consistent with preclinical findings, observations from the HALO-109-101 and HALO-109-102 phase 1 trials, PEGPH20 increased plasma HA and tumor permeability, while decreasing tumor metabolic activity [ 19 ]. These results led to the randomized phase 2 trial, where patients with treatment naïve metastatic PDA received gemcitabine/nab-paclitaxel alone or in combination with PEGPH20 [ 20 , 21 ] ( Table 1 ). Correlative work included baseline tumor HA level assessment, where HA levels were categorized as HA low or HA high , which was defined by HA staining in the ECM as <50% or ≥50% of tumor surface, respectively.…”

Section: Targeting Pancreatic Cancer Stromamentioning

confidence: 99%

Emerging Therapies and Future Directions in Targeting the Tumor Stroma and Immune System in the Treatment of Pancreatic Adenocarcinoma

Ahn

Ramanathan

Bekaii‐Saab

2018

Cancers

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Pancreatic adenocarcinoma is typically refractory to conventional treatments and associated with poor prognosis. While therapeutic advances over the past several years have improved patient outcomes, the observed benefits have been modest at best, highlighting the need for continued development of alternate treatment strategies. The tumor microenvironment has been identified as being integral to oncogenesis through its direct effect on cellular pathway communication, immune inhibition, and promoting chemo-resistance. A more in depth understanding of the biology of the disease, in addition with our ability to develop more effective novel therapies have led to ongoing studies that are investigating several promising treatment options in this disease. Herein, we highlight and review the therapeutic landscape in pancreatic adenocarcinoma.

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“…The delivery mechanisms of Abraxane are thought to be mediated by passive targeting tumors by the EPR effect through the leaky tumor vessels and active targeting to the serum protein acidic and rich in cysteine [72]. The observed efficacy in pancreatic cancer therapy is also considered to be mediated by disrupting the tumor stroma from the initial nanoparticle-drug delivery that further increases drug delivery into the tumor [73–76]. Preclinical studies showed that modification of the human albumin-paclitaxel nanoparticles by conjugating tumor necrosis factor-related apoptosis-inducing ligand [77] or RGD integrin targeting ligand [76] enhanced the therapeutic effect.…”

Section: Current Advances In Cancer Nanotechnology For Detection and mentioning

confidence: 99%

“…It was also reported that albumin-bound formulation of paclitaxel nanoparticles in the combination with other chemotherapy drugs, such as gemcitabine, significantly increased overall survival of pancreatic cancer patients with metastatic diseases [78]. Another promising clinical trial for pancreatic cancer therapy involved co-delivering chemotherapy agents with Peglyated hyaluronidase (PEGrHuPH20) [73]. Delivery of PEGrHuPH20 into pancreatic cancer tissues leads to the degradation of extracellular matrix, hyaluronic acid, in the tumor stroma and reduction of the interstitial pressure, allowing improved drug delivery into the tumor bed and enhanced therapeutic responses.…”

Section: Current Advances In Cancer Nanotechnology For Detection and mentioning

confidence: 99%

Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy

et al. 2017

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Pancreatic cancer remains one of the major causes of cancer-related mortality. The majority of pancreatic cancer patients are diagnosed at the advanced stage with unresectable and drug resistant tumors. The new treatments with the combination of chemotherapy, molecular targeted therapy, and immunotherapy have shown modest effects on therapeutic efficacy and survival of the patients. Therefore, there is an urgent need to develop effective therapeutic approaches targeting highly heterogeneous pancreatic cancer cells and tumor microenvironments. Recent advances in biomarker targeted cancer therapy and image-guided drug delivery and monitoring treatment response using multifunctional nanoparticles, also referred to as theranostic nanoparticles, offer a new opportunity of effective detection and treatment of pancreatic cancer. Increasing evidence from preclinical studies has shown the potential of applications of theranostic nanoparticles for designing precision oncology approaches for pancreatic cancer therapy. In this review, we provide an update on the current understanding and strategies for the development of targeted therapy for pancreatic cancer using nanoparticle drug carriers. We address issues concerning drug delivery barriers in stroma rich pancreatic cancer and the potential approaches to improve drug delivery efficiency, therapeutic responses and tumor imaging. Research results presented in this review suggest the development of an integrated therapy protocol through image-guided and targeted drug delivery and therapeutic effect monitoring as a promising precision oncology strategy for pancreatic cancer treatment.

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Final analysis of stage 1 data from a randomized phase II study of PEGPH20 plus nab-Paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients (pts), utilizing Ventana companion diagnostic assay.

Cited by 10 publications

References 0 publications

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Emerging Therapies and Future Directions in Targeting the Tumor Stroma and Immune System in the Treatment of Pancreatic Adenocarcinoma

Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy

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