Efficacy and Safety of L-asparaginase Encapsulated in RBC Combined With Gemcitabine or FOLFOX in 2nd Line for Progressive Metastatic Pancreatic Carcinoma

Study Overview
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Brief Summary
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A new approach that aims to destroy pancreatic tumor cells through modification of the tumor environment. Asparagine synthetase (ASNS) is an enzyme wich synthetise asparagine. Asparagine is an essential nutriment for pancreatic cancer cells which have no or low level of ASNS. by L-asparaginase encapsulated in erythrocytes deplete (supress) Plasma asparagine. in selected patients having no or low ASNS, may provide a new therapeutic approach.

Official Title
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Phase II, Randomized, Controlled, Clinical Trial Exploring Efficacy and Safety of ERY001 (L-asparaginase Encapsulated in Red Blood Cells) in Association With Gemcitabine or FOLFOX4 in Second-line Therapy for Patients With Progressive Metastatic Pancreatic Carcinoma

Conditions
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Pancreatic Adenocarcinoma Metastatic

Intervention / Treatment
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* Drug: ERY001
* Drug: Gemcitabine
* Drug: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient is eligible for the study if all of the following criteria are met: Advanced or metastatic exocrine pancreatic adenocarcinoma, confirmed histologically Available archival tumor tissue block with sufficient tissue either from primary tumor and/or from metastatic lesions for biomarker testing; alternatively, unstained slides with sufficient tissue may be substituted Only 1 prior systemic therapy for advanced or metastatic disease. NOTE: Patient must be eligible to 2nd line gemcitabine or mFOLFOX6 treatment Documented disease progression during or following first-line therapy for advanced disease Measurable lesion (>1cm) as assessed by CT scan or MRI (Magnetic Resonance Imaging) according to RECIST criteria (version 1.1) Age 18 years and older ECOG performance status 0 or 1 Ability to understand, and willingness to sign, a written informed consent and to comply with the scheduled visits, treatment plans, laboratory tests, and other study procedures. Patient beneficiary of a Social Security Insurance if applicable Exclusion Criteria: A patient is excluded from the study if any of the following criteria are met: Patient who have received Oxaliplatin in first line will not be eligible in FOLFOX arm; Patient who received Gemcitabine in first line will not be eligible in Gemcitabine arm Resectable pancreatic adenocarcinoma Known hypersensitivity to L-asparaginase or have had prior exposure to any form of L-asparaginase Anti-vitamin K treatment. Replacement with low molecular weight heparin treatment if required Inadequate organ functions: hemoglobin < 9.0 g/dl, neutrophil count < 1.5 x 109/L, platelets < 100 x 109/L. Liver or pancreatic function abnormalities AST or ALT > 3 x ULN, or Total bilirubin > 1.5 x ULN, or Lipase > 2 x ULN with suggestive clinical sign of pancreatitis or > 3N without suggestive clinical sign Renal insufficiency: Renal clearance determined by the Cockroft and Gault Formula < 60 mL/min Current or prior coagulopathy disorders in the last month PT ≥1.5 fold the upper limit of normal value or INR ≥1.5 fold the upper limit of normal value or Fibrinogen ≤ 0.75 fold the lower limit of normal value Known Infection: HIV, active hepatitis related to B or C virus Concurrent active malignancies (with the exception of in situ carcinoma of the cervix and inactive non melanoma skin cancer Other serious conditions than pancreatic cancer according to investigator's opinion NYHA Grade ≥ 2 congestive heart failure Systemic chemotherapy or radiation within the last 3 weeks or major surgery within 4 weeks NOTE: chemotherapy or radiation therapy given in less than 3 weeks is allowed, provided patient recovered from all related toxicities History of grade 3 blood transfusion reaction (life threatening situation) Presence of anti-erythrocyte antibodies (auto-antibodies or anti-public antibodies) preventing from getting a compatible packed Red Blood Cells for the patient Participation in another concurrent clinical trial Women of child-bearing potential and men with partners of childbearing potential without effective contraception as well as pregnant or breast feeding women Other severe acute/chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: standard of care combined with ERY001<br>standard of care = Gemcitabine or folfox | Drug: ERY001<br> <br> * Other names: L asparaginase encapsulated in erythrocytes;Drug: Gemcitabine<br> <br> Drug: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)<br>* oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2<br>|
| Sham Comparator: standard of care alone<br>standard of care = Gemcitabine or folfox | Drug: Gemcitabine<br> <br> Drug: 5-fluoro-uracil/oxaliplatin/leucovorin (folfox)<br>* oxaliplatin 85 mg/m2 levo-leucovorin 200 mg/m2 5-FU 400 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Evaluate the effects of eryaspase when combined with chemotherapy for the second line treatment of patients with pancreatic adenocarcinoma in terms of OS, whose tumors has low or no ASNS expression (ASNS 0 or 1+) | From last study treatment assessment visit until patient's death, loss to follow up, or study closure, assessed up to 36 months. | 
| Progression free survival (PFS) | Evaluate the effects of eryaspase when combined with chemotherapy for the second line treatment of patients with pancreatic adenocarcinoma in terms of PFS, whose tumors has low or no ASNS expression (ASNS 0 or 1+) | From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | Compare the safety profile in patients treated with eryaspase in combination with chemotherapy versus chemotherapy alone, including adverse events, vital signs and clinical laboratory assessments | collected from time of informed consent until 4 weeks after last study treatment | 
| Overall survival | Evaluate the effects of eryaspase in combination with chemotherapy on investigator-assessed OS in all randomized patients (all patients) and in patients with ASNS 2+/3+ expressing tumors. | From last study treatment assessment visit until patient's death, loss to follow up, or study closure, assessed up to 36 months. | 
| Progression free survival | Evaluate the effects of eryaspase in combination with chemotherapy on investigator-assessed PFS in all randomized patients (all patients) and in patients with ASNS 2+/3+ expressing tumors. | From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months. | 
| Objective response rate (ORR) | Evaluate the effect of eryaspase in combination with chemotherapy on the ORR, and the duration in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors. | From date of randomization to last tumor assessment data collected for each patient, assessed up to 24 months. | 
| Disease control rate (DCR) | Evaluate the effect of eryaspase in combination with chemotherapy on the DCR in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors. | From date of randomization to 16 and 24 weeks. | 
| Duration of response (DoR) | Evaluate the effect of eryaspase in combination with chemotherapy on the DoR in all comers, patients with ASNS 0/1+ expressing tumors, and those with ASNS 2+/3+ expressing tumors. | From date of first response of complete or partial response until tumor progression, assessed up to 24 months. | 
| Evaluate the relationship of clinical outcomes with tumor markers | Evaluate the relationship of clinical outcome (i.e. OS, PFS, ORR, DCR and DoR) with tumor markers, namely cancer antigen (CA19-9), and carcinoembryonic antigen test (CEA). | From date of randomiztion to end of treatment visit, assessed up to 20 months. | 
| Optical density reading | Assess the effect of eryaspase in combination with chemotherapy on PFS, OS, ORR, BOR, and other clinical outcomes in ASNS subsets, as determined by optical density reading. | From date of randomization to first documented progression of disease, death for any cause or until start of new anti-cancer treatment, whcihever came first, assessed up to 24 months. | 
| Quality of Life status | Compare the 2 treatment arms with respect to change in quality of life status, the change of QOL relative to baseline | From date of randomiztion to end of treatment visit, assessed up to 20 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, Pancreas, adenocarcinoma, asparaginase, erythrocytes, red blood cell, Encapsulation, folfox, gemcitabine