A Pilot Trial of PEGPH20 (Pegylated Hyaluronidase) in Combination With Avelumab (Anti-PD-L1 MSB0010718C) in Chemotherapy Resistant Pancreatic Cancer
试验速览
- 阶段
- 早期 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 7
- 试验地点
- 3
- 主要终点
- Determine ORR as per RECIST v1.1 criteria
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Performance-status ECOG 0 -
- •Life expectancy ≥ 3 months.
- •Resolved acute effects of any prior therapy to baseline or Grade ≤1 severity
- •Screening laboratory:
- •Hematologic: ANC ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL
- •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)
- •Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula or serum creatinine ≤ 2.0 mg/dL.
- •Albumin ≥2.5 g/dL.
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: PEGylated Recombinant Human Hyaluronidase (PEGPH20) (Drug)
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.
干预措施: Avelumab (Drug)
结局指标
主要结局
Determine ORR as per RECIST v1.1 criteria
时间窗: 6 months from trial treatment initiation cycle 1/day 1. Each treatment cycle is 14 days
Determine ORR as per RECIST v1.1 criteria
To assess the safety of this combination in patients with PDAC.
时间窗: Initiation of trial treatment cycle 1/day 1 through 30 days after last dose of trial treatment
graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03
次要结局
- Determine OS (OVERALL SURVIVAL)(From date of treatment initiation cycle 1/day 1 until death from any cause, assessed up to 36 months)
- Determine PFS (PROGRESSION FREE SURVIVAL)(From date of treatment initiation cycle 1/day 1 until progression, assessed up to 24 months)
- Changes in CA 19,9 leves(Up to 4 weeks)