A Trial of PEGPH20 in Combination With Avelumab in Chemotherapy Resistant Pancreatic Cancer

A Pilot Trial of PEGPH20 (Pegylated Hyaluronidase) in Combination With Avelumab (Anti-PD-L1 MSB0010718C) in Chemotherapy Resistant Pancreatic Cancer

The purpose of this study is to evaluate the pharmacodynamics, safety and efficacy of PEGPH20 in combination with Avelumab in adult patients with chemotherapy resistant advanced or locally advanced pancreatic ductal adenocarcinoma (PDAC). This is a multi-center, open-label, non-randomized trial.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: PEGylated Recombinant Human Hyaluronidase (PEGPH20); Drug: Avelumab

Detailed Description

The reported response rate with check-point inhibitors in PDAC is 0 %. This study tests the hypothesis that elimination of HA in pancreas tumor microenvironment mediated by PEG PH20 will result in increased tumor vascularization and vessel patency as well as stromal remodeling with increase immune infiltrate. These effects may facilitate the activity of check-point inhibitors like avelumab by at least two mechanisms including increase in drug delivery and increasing immune infiltrate.

The purpose of this study is to evaluate the pharmacodynamics, safety and efficacy of PEGPH20 in combination with Avelumab in adult patients with chemotherapy resistant advanced or locally advanced pancreatic ductal adenocarcinoma (PDAC). This is a multi-center, open-label, non-randomized trial.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid
    • Fuenlabrada, Madrid, Spain
      • Hospital Universitario Fuenlabrada

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Signed, written IRB/IEC-approved Informed Consent Form
• Histologically or cytologically-confirmed pancreatic ductal adenocarcinoma (PDAC).
• Accessible tumor for two repeated tumor biopsies.
• Progression to first line treatment for locally advanced or advanced disease. Prior adjuvant chemotherapy or chemoradiation therapy for early disease is allowed.
• Age ≥18 years.
• Radiologically measurable disease per RECIST v1.1.
• Performance-status ECOG 0 -2.
• Life expectancy ≥ 3 months.
• Resolved acute effects of any prior therapy to baseline or Grade ≤1 severity

• Screening laboratory:

  1. Hematologic: ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL
  2. Hepatic: Total bilirubin level ≤ 1.5 × the ULN range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 X ULN (for subjects with documented metastatic disease to the liver)
  3. Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula or serum creatinine ≤ 2.0 mg/dL.
  4. Albumin ≥2.5 g/dL.
  5. Coagulation: PT time and INR within normal limits (+/-15%). PTT within normal limits (+/-15%).
• If a subject requires anticoagulation, treatment must be modified to enoxaparin.
• Negative serum pregnancy test if female subject is of childbearing potential.
• Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, biopsies when required, and other procedures.

Exclusion Criteria:

• Clinical evidence of DVT, PE, prior history of CVA or history of TIA within 12 months or other known TE event present during the screening period
• Current use of megestrol acetate (use within 10 days of Day 1).
• Contraindication to heparin as per institutional guidelines.
• Another primary cancer within the last 3 years currently requiring antineoplastic treatment within the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ.
• Current use of immunosuppressive medication within 2 weeks of study participation, EXCEPT for those listed in protocol
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent: Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
• Prior organ transplantation including allogenic stem-cell transplantation.
• Active infection requiring systemic therapy.
• Known infection with human immunodeficiency virus, Hepatitis B, or Hepatitis C
• Known prior severe hypersensitivity to investigational product, hyaluronidase, or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3).
• Any history of anaphylaxis or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Clinically significant (i.e., active) cardiovascular disease: myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
• Prior cerebrovascular accident/stroke.
• Clinically significant carotid artery disease (e.g. prior carotid surgery, symptomatic and/or requires treatment)
• Inability to comply with study and follow-up procedures as judged by the Investigator.
• Known alcohol or drug abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PEGPH20 + Avelumab; PEGPH20, a multi-site PEGylated enzyme generated by conjugating N-hydroxysuccinimidyl ester of methoxypoly(ethylene glycol)-butanoic acid (MSBA30K/B or PEG) and recombinant human hyaluronidase (rHuPH20). PEGPH20 has a half-life of approximately 2 days, thereby enabling systemic activity and sustained duration of action to degrade HA. In many different tumor types tested in murine xenograft models, response to PEGPH20 has been shown to be more robust for tumors characterized by higher HA expression.

Drug: PEGylated Recombinant Human Hyaluronidase (PEGPH20); PEGPH20 will be administered at a dose of 3.0 micrograms per kilogram (μg/kg) as an intravenous (IV) infusion.; Drug: Avelumab; Avelumab will be administered as at a dose of 10 milligrams per kilogram (mg/kg) as an intravenous (IV) infusion once every 2 weeks.; Other Names: MSB0010718C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine ORR as per RECIST v1.1 criteria	Determine ORR as per RECIST v1.1 criteria	6 months from trial treatment initiation cycle 1/day 1. Each treatment cycle is 14 days
To assess the safety of this combination in patients with PDAC.	graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03	Initiation of trial treatment cycle 1/day 1 through 30 days after last dose of trial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine OS (OVERALL SURVIVAL)	The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive	From date of treatment initiation cycle 1/day 1 until death from any cause, assessed up to 36 months
Determine PFS (PROGRESSION FREE SURVIVAL)	The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.	From date of treatment initiation cycle 1/day 1 until progression, assessed up to 24 months
Changes in CA 19,9 leves	Measured in UI/ML	Up to 4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of PEGPH20 in tumor hyaluronic acid (HA) content in plasma and paired tumor biopsies of patients with PDAC treated with this regimen	Hyaluronan concentrations will be analyzed in blood plasma samples by total HA disaccharides using liquid chromatography-tandem mass spectrometry (LC-MS-MS) . Hyaluronan concentrations will be analyzed in tumor tissue samples using an immunohistochemical method used exclusively in research.	tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
Collagen content	Collagen type I will be determine in tumor samples	tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
Cancer associated fibroblasts (CAF) in tumor samples.	Activated fibroblasts will be determined with double staining using vimentin as a fibroblast total marker and smooth muscle actin (SMA) as an activated fibroblast marker.	tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
Immune infiltrate.	CD4 and CD8 surface markers will be used to determine the immune infiltrate in tumor samples.	tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months

Collaborators and Investigators

• Sponsor: PH Research, S.L.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2018
• Primary Completion (Actual): January 10, 2019
• Study Completion (Actual): June 10, 2019

Study Registration Dates

• First Submitted: February 10, 2018
• First Submitted That Met QC Criteria: March 22, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2019
• Last Update Submitted That Met QC Criteria: August 20, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: pancreatic cancer, inmunotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Avelumab
• Other Study ID Numbers: PH1603

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No