Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase)in Patients With Pancreatic Cancer

Study Overview
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Brief Summary
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The interest in using L-asparaginase in pancreatic cancer arose from in vitro and in vivo studies data showing an anti-neoplastic effect on pancreatic tumor cell lines. Interestingly, these studies suggest an additional effect of L-asparaginase associated to gemcitabine.GRASPA is a suspension of red blood cells encapsulating L-asparaginase. The aim of this phase I clinical trial is to evaluate the Maximum Tolerated Dose (MTD) of GRASPA on locally advanced or metastatic pancreatic tumors, after therapy failure of first or second line chemotherapy using gemcitabine.

Official Title
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Phase I, Dose Escalation Clinical Trial of GRASPA (Red Blood Cells Encapsulating L-Asparaginase) in Patients With Pancreatic Carcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: GRASPA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Exocrine pancreatic adenocarcinoma cytologically or histologically confirmed Locally advanced and non-resectable with invasion of the superior mesenteric artery (stage III) or metastatic (stage IV) as defined by TNM (primary tumor, regional nodes, metastasis) 2002 classification (UICC 2002) resistant to a first or second line chemotherapy with gemcitabine Patient aged between 18 to 70 years Signed Informed Consent Form Life expectancy ≥ 12 weeks Accurate measurement of tumor volume by imagery (in at least one dimension) Presence of one or several tumor markers (carcinoembryonic antigen [CEA] and cancer antigen [CA] 19.9) Eastern Cooperative Oncology Group [ECOG] Prognostic Score : 0, 1 or 2 Patient beneficiary of a Social Security Insurance Exclusion Criteria: Patient with an endocrine or acinar pancreatic tumor Patient with known or suspected cerebro-meningeal metastases Haemoglobin level greater than 13 g/L Patient hypersensitive to L-asparaginase or have had prior exposure to any form of L-asparaginase Splenic vein thrombosis < 3 months or under active treatment Anti-vitamin K treatment Hepatic Insufficiency unrelated to pancreatic cancer Renal insufficiency unrelated to pancreatic cancer Pancreatitis or pancreatitis history unrelated to pancreatic cancer Insulin-dependant diabetes mellitus unrelated to pancreatic cancer Current or prior coagulopathy disorders unrelated to pancreatic cancer ECOG Prognostic Score 3 or 4 History of grade 3 blood transfusion reaction (life threatening situation) Presence of rare and dangerous anti-erythrocyte antibodies preventing from getting a compatible packed Red Blood Cells for the patient Patient already included in another clinical trial Pregnancy, breast-feeding or absence of secured contraception Unwillingness to sign the informed consent form

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRASPA 25<br> | Drug: GRASPA<br>* Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA will be administered to cohorts of 3 patients per dose<br>|
| Experimental: GRASPA 50<br> | Drug: GRASPA<br>* Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA will be administered to cohorts of 3 patients per dose<br>|
| Experimental: GRASPA 100<br> | Drug: GRASPA<br>* Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA will be administered to cohorts of 3 patients per dose<br>|
| Experimental: GRASPA 150<br> | Drug: GRASPA<br>* Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA will be administered to cohorts of 3 patients per dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose-limiting Toxicities up to Week 4 After Treatment | Dose limiting toxicities were defined according to CTCAE v3.0 as follow: Known toxicities related to asparaginase: Pancreatic grade 2, 3 or 4 Allergic, Neurological, Hepatic, Coagulation grade 3 or 4 an any other toxicity of grade 4 | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Limiting Toxicities From Week 4 to Week 8 (End of Study) | Limiting toxicities were defined according to CTCAE v3.0 as follow: Known toxicities related to asparaginase: Pancreatic grade 2, 3 or 4 Allergic, Neurological, Hepatic, Coagulation grade 3 or 4 Any other toxicity of grade 4 | 8 weeks | 
| Encapsulated L-asparaginase Pharmacokinetic Parameters Terminal Half-life | Pharmacokinetic (PK) parameters were analyzed for encapsulated asparaginase concentration data using Phoenix® WinNonlin® 6.3. Free and total L-asparaginase activity was measured during the study and encapsulated asparaginase was defined as the difference between total asparaginase and plasmatic asparaginase. | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 | 
| Encapsulated L-asparaginase Pharmacokinetic Parameters Cmax | Pharmacokinetic (PK) parameters were analyzed for encapsulated asparaginase concentration data using Phoenix® WinNonlin® 6.3. Free and total L-asparaginase activity was measured during the study and encapsulated asparaginase was defined as the difference between total asparaginase and plasmatic asparaginase. | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 | 
| Encapsulated L-asparaginase Pharmacokinetic Parameters Area Under the Curve to Infinity | Pharmacokinetic (PK) parameters were analyzed for encapsulated asparaginase concentration data using Phoenix® WinNonlin® 6.3. Free and total L-asparaginase activity was measured during the study and encapsulated asparaginase was defined as the difference between total asparaginase and plasmatic asparaginase. | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 | 
| Change of Asparagine Levels From Baseline (Pharmacodynamics) | Duration of plasma asparagine depletion (less than or equal to 2 micromoles/Liter or deamination greater than 90% compared to baseline levels and serum concentrations of L-asparagine, L-aspartate, L-glutamine, and L-glutamate. For pharmacodynamic data, the administration date of the investigational treatment was considered as the reference date for duration calculation. All patients having received a single dose of studied drug GRASPA have been analyzed. | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 | 
| Number of Patient Positive for Anti-L-asparaginase Antibodies | Titers of E. coli anti-asparaginase antibodies evaluated over time to assess immunogenicity | Day 0, 1, 28 and 56 | 
| Summary of CEA Level Over Time | Assess tumor response, evaluated by carcinoembryonic antigen (CEA) tumor marker evolution | Day 0, 28, 56 | 
| Summary of CA 19.9 Over Time | Tumor response Evaluation by cancer antigen (CA)19.9 evolution over time | Day 0, 28 and 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic cancer, asparaginase