pegvorhyaluronidase alfa (PEGPH20) / Halozyme, Nektar Therap - LARVOL DELTA

Pancreatic Neuroendocrine Tumors Secrete Apolipoprotein E to Induce Tip Endothelial Cells That Remodel the Tumor-Stroma Ratio and Promote Cancer Progression. (PubMed, Cancer Res) - "Importantly, mTOR inhibitors synergistically enhanced the antitumor effects of stroma-targeting PEGPH20 in vivo in pNETs. Overall, this study revealed that cancer cell-derived ApoE could induce TipECs to remodel the TSR and that mTOR inhibitors could increase the efficacy of stroma-targeting therapies. Secretion of ApoE by pancreatic neuroendocrine tumor cells engenders a stroma-rich microenvironment, which can be reversed with mTOR inhibitors as part of combination strategies targeting the tumor stroma."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • APOE • ATF6 • SCARB1

MORPHEUS-EC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer) (clinicaltrials.gov) - P1/2 | N=410 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2025 ➔ Sep 2025 | Trial primary completion date: Jun 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • HER-2 • PD-L1 • TIGIT

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=341 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Tumour-derived apolipoprotein E induces tip endothelial cell to remodel tumour stroma ratio and promote pancreatic neuroendocrine tumour progression (ENETS 2025) - "Importantly, mTOR inhibitors effectively compensated for the absence of the anti-stroma PEGPH20 in pNETs. CONCLUSION Our study reveals that tumour-derived APOE could induce TipECs to remodel TSR, and mTOR inhibitors could enhance the efficacy of the anti-stroma PEGPH20."

Stroma • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • APOE • CAFs

siRNA-Encapsulated Biomimetic Liposomes Effectively Inhibit Tumor Cells' Hexosamine Biosynthesis Pathway for Attenuating Hyaluronan Barriers to Pancreatic Cancer Chemotherapy. (PubMed, ACS Nano) - "In combination with Doxil, PMLip@siGFAT1 demonstrated potent antitumor efficacy with minimal systemic toxicity. Importantly, unlike PEGPH20 (hyaluronidase), PMLip@siGFAT1 reduced tumor invasiveness, while preserving skeletal muscle integrity. These findings highlight that PMLip@siGFAT1 holds great potential to revitalize HA downregulation strategies in pancreatic cancer for enhanced drug delivery and efficacy."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2026 ➔ Jan 2025 | Trial primary completion date: Oct 2025 ➔ Jan 2025

Metastases • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Investigational Use of Real-World Data as a Hybrid Control in Pancreatic Ductal Adenocarcinoma from the Randomized Phase Ib/II MORPHEUS Trial. (PubMed, Clin Pharmacol Ther) - "The RCT experimental arm (atezolizumab + PEGylated recombinant human hyaluronidase (Atezo + PEGPH20)) was compared with an HC arm consisting of patients treated with modified FOLFOX6 or gemcitabine/nab-paclitaxel from the MORPHEUS PDAC internal control arm supplemented with data from a nationwide EHR-derived de-identified database as the EC arm. The direction and magnitude of hazard ratios (HRs) from the multiple HC analyses (HRs ranged from 1.02 to 1.06) were comparable with the reported trial HR (HR 0.91; 95% CI: 0.56, 1.49). This analysis demonstrates the feasibility and applicability of leveraging RWD in clinical trial design to supplement clinical trial control arms."

Journal • P1/2 data • Real-world • Real-world evidence • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

MORPHEUS-EC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer) (clinicaltrials.gov) - P1/2 | N=410 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Aug 2024 ➔ Apr 2025

Metastases • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PD-L1 • TIGIT

Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer. (PubMed, Biomed Pharmacother) - "These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC."

Journal • Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD31 • PECAM1

Study Of Gemcitabine, Nab-paclitaxel, PEGPH20 and Rivaroxaban for Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P=N/A | N=110 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Limiting Extracellular Matrix Expansion in Diet-Induced Obese Mice Reduces Cardiac Insulin Resistance and Prevents Myocardial Remodelling. (PubMed, Mol Metab) - "Our results provide important new insights into the role of ECM deposition in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications."

Journal • Preclinical • Cardiovascular • Genetic Disorders • Heart Failure • Obesity • MMP9

Magnetic resonance imaging of tumor response to stroma-modifying pegvorhyaluronidase alpha (PEGPH20) therapy in early-phase clinical trials. (PubMed, Sci Rep) - P1, P1b/2 | "A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies."

Journal • MRI • Stroma • Oncology • Solid Tumor

S1313, PEGPH20 in Treating Patients With Newly Diagnosed Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=126 | Completed | Sponsor: SWOG Cancer Research Network | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Monitor PDAC Tumor Response to Stroma-Targeting Therapy using CEST MRI (RSNA 2023) - "We have evaluated dextran-enhanced CEST MRI’s ability to assess tumor responses to stroma-targeting therapy. Our data indicates that 10 kD dextran is suitable for monitoring the tumor responses to PEGPH20. Reference : 1."

Stroma • Fibrosis • Gastrointestinal Cancer • Mood Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

MORPHEUS-GC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer) (clinicaltrials.gov) - P1/2 | N=410 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PD-L1 • TIGIT

S1313, PEGPH20 in Treating Patients With Newly Diagnosed Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=126 | Active, not recruiting | Sponsor: SWOG Cancer Research Network | Trial completion date: Jul 2023 ➔ Dec 2023

Metastases • Trial completion date • Gastrointestinal Cancer • Hepatology • Neutropenia • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2024 ➔ Oct 2026 | Trial primary completion date: Jun 2024 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Study Of Gemcitabine, Nab-paclitaxel, PEGPH20 and Rivaroxaban for Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P=N/A | N=110 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Oct 2024

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer. (PubMed, Mol Imaging Biol) - "Our results suggest that k derived from SSM and V from ETM, both using group AIF, are optimal for the detection of microvascular changes induced by stroma-directed drug PEGPH20. These analyses provide insights in the choice of PK model and AIF for optimal DCE protocol design in mouse pancreatic cancer models."

Journal • PK/PD data • Preclinical • Stroma • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Investigating the contribution of hyaluronan to the breast tumour microenvironment using multiparametric MRI and MR elastography. (PubMed, Mol Oncol) - "Treatment of MDA-MB-231 LM2-4 tumours reduced ADC and dramatically increased tumour viscoelasticity measured by MR elastography. Correlation matrix analyses of data from all models identified ADC as having the strongest correlation with HA accumulation, suggesting that ADC is the most sensitive imaging biomarker of tumour response to PEGPH20."

Journal • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • HAS 3

Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform. (PubMed, Oncologist) - P1/2 | "Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369)."

Journal • Metastases • P1/2 data • Gastric Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

PEGPH20 improves pfs in patients with metastatic pancreatic ductal adenocarcinoma: A randomized phase 2 study in combination with nab-paclitaxel/gemcitabine (ESMO-GI 2017) - P2; "Randomized Phase 2 study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection for PEGPH20, currently investigated in the ongoing global Phase 3 HALO 301 study with PFS and OS as co-primary endpoints. NCT01839487"

Biomarker • Clinical • Combination therapy • P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Tumor Hyaluronan May Predict Benefit From PEGPH20 When Added to nab Paclitaxel/Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma (mPDA) (ESMO-GI 2017) - P2; "This is the first randomized Phase 2 study evaluating and supporting tumor HA as a potential predictive biomarker informing patient selection for PEGPH20 treatment, based on improvement in both PFS and OS in HA-High pts. The results provide support for the ongoing Phase 3 HALO 109-301 study with co-primary endpoints of PFS and OS. NCT01839487."

Biomarker • Clinical • Pancreatic Cancer

Phase 3, randomized, double-blind, placebo-controlled study of PEGylated recombinant human hyaluronidase PH20 (PEGPH20)+nab-paclitaxel/gemcitabine in patients with previously untreated, hyaluronan-high, stage IV pancreatic ductal adenocarcinoma (PDA) (ESMO Asia 2017) - P3; "Dexamethasone is given before and after PEGPH20 to reduce treatment‑related musculoskeletal symptoms and enoxaparin is given to minimize thromboembolic events. Adverse events will be graded per NCI CTCAE v4.03. An independent Data Monitoring Committee will evaluate safety and efficacy (PFS and OS) data."

P3 data • Retrospective data • Pancreatic Cancer