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

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

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: GRASPA

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GRASPA 25	Drug: GRASPA; 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
Experimental: GRASPA 50	Drug: GRASPA; 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
Experimental: GRASPA 100	Drug: GRASPA; 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
Experimental: GRASPA 150	Drug: GRASPA; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ERYtech Pharma

Publications and helpful links

General Publications

• Bachet JB, Gay F, Marechal R, Galais MP, Adenis A, MsC DS, Cros J, Demetter P, Svrcek M, Bardier-Dupas A, Emile JF, Hammel P, Ebenezer C, Berlier W, Godfrin Y, Andre T. Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma. Pancreas. 2015 Oct;44(7):1141-7. doi: 10.1097/MPA.0000000000000394.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (Estimate): February 1, 2012

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: pancreatic cancer; asparaginase
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms
• Other Study ID Numbers: GRASPANC2008-02