Clinical trial NCT03481920: A Trial of PEGPH20 in Combination With Avelumab in Chemotherapy Resistant Pancreatic Cancer
Official title: A Pilot Trial of PEGPH20 (Pegylated Hyaluronidase) in Combination With Avelumab (Anti-PD-L1 MSB0010718C) in Chemotherapy Resistant Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Pancreatic Ductal Adenocarcinoma
Pancreatic Cancer
Keywords: pancreatic cancer, inmunotherapy
Lead sponsor: PH Research, S.L.
Sponsor class: OTHER
First posted: 2018-03-29
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Determine ORR as per RECIST v1.1 criteria
timeFrame: 6 months from trial treatment initiation cycle 1/day 1. Each treatment cycle is 14 days
measure: To assess the safety of this combination in patients with PDAC.
timeFrame: Initiation of trial treatment cycle 1/day 1 through 30 days after last dose of trial treatment
Secondary outcomes:
measure: Determine OS (OVERALL SURVIVAL)
timeFrame: From date of treatment initiation cycle 1/day 1 until death from any cause, assessed up to 36 months
measure: Determine PFS (PROGRESSION FREE SURVIVAL)
timeFrame: From date of treatment initiation cycle 1/day 1 until progression, assessed up to 24 months
measure: Changes in CA 19,9 leves
timeFrame: Up to 4 weeks
Other outcomes:
measure: The effect of PEGPH20 in tumor hyaluronic acid (HA) content in plasma and paired tumor biopsies of patients with PDAC treated with this regimen
timeFrame: tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
measure: Collagen content
timeFrame: tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
measure: Cancer associated fibroblasts (CAF) in tumor samples.
timeFrame: tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
measure: Immune infiltrate.
timeFrame: tumor assessments performed every 8 +/- 1 week while on treatment, up to 24 months
Locations:
city: Fuenlabrada
country: Spain
facility: Hospital Universitario Fuenlabrada
state: Madrid
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
Study officials:
References: