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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GRASPA 25 | Experimental |
| |
| GRASPA 50 | Experimental |
| |
| GRASPA 100 | Experimental |
| |
| GRASPA 150 | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GRASPA | Drug | 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 |
|
| 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:
| 4 weeks |
| 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:
| 8 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26355551 | Derived | 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. |
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This was not a randomized study. No washout or run-in was required. Assignment of patients to treatment groups followed study design rules, per protocol.
Participants were recruited at 3 investigational sites in France between November 2009 and February 2011. The first participant was enrolled in the study on 27 November 2009 and the last patient exited the study on 30 March 2011.
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| ID | Title | Description |
|---|---|---|
| FG000 | GRASPA 25 | 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 |
| FG001 | GRASPA 50 | 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 |
| FG002 | GRASPA 100 | 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 |
| FG003 | GRASPA 150 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | GRASPA 25 | Participants received one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA was administered to cohorts of 3 patients per dose 3 subjects enrolled; 0 subjects completed |
| BG001 | GRASPA 50 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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:
| Posted | Number | participants | 4 weeks |
|
Reported Adverse Events (AEs) include events starting from patient inclusion until 2 month after GRASPA administration (~2.5 months)
Adverse events regardless of grade or causality are reported. Events are summarized by system organ class and footnote indicates the specific events reported for each class.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | GRASPA 25 | 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 3 subjects enrolled; 0 subjects completed |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspnea related to pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (14.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of Clinical Trials | Erytech Pharmaceuticals | +33 4 78 74 44 38 | contact@erytech.com |
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| ID | Term |
|---|---|
| D010190 | Pancreatic Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
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| 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 |
Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA was administered to cohorts of 3 patients per dose
3 subjects enrolled; 3 subjects completed
| BG002 | GRASPA 100 | Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA was administered to cohorts of 3 patients per dose 3 subjects enrolled; 1 subject completed |
| BG003 | GRASPA 150 | Each patient will receive one administration of GRASPA . A stepwise increase of 4 single doses of GRASPA was administered to cohorts of 3 patients per dose 3 subjects enrolled; 0 subjects completed |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG002 | GRASPA 100 | 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 3 subjects enrolled; 1 subject completed |
| OG003 | GRASPA 150 | 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 3 subjects enrolled; 0 subjects completed |
|
|
| Secondary | 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:
| AEs that met the following criteria were considered for the primary safety criterion:
| Posted | Count of Participants | Participants | 8 weeks |
|
|
|
| Secondary | 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. | Data were available for dose levels (no. of patients) of 25 IU/kg (n=1), 50 IU/kg (n=0), 100 IU/kg (n=0), and 150 IU/kg (n=3). | Posted | Mean | Standard Deviation | days | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 |
|
|
|
| Secondary | 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. | Data were available for dose levels (no. of patients) of 25 IU/kg (n=1), 50 IU/kg (n=0), 100 IU/kg (n=0), and 150 IU/kg (n=3). | Posted | Mean | Standard Deviation | IU/L | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 |
|
|
|
| Secondary | 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. | Data were available for dose levels (no. of patients) of 25 IU/kg (n=1), 50 IU/kg (n=0), 100 IU/kg (n=0), and 150 IU/kg (n=3). | Posted | Mean | Standard Deviation | hr*IU/L | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 |
|
|
|
| Secondary | 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. | 12 patients were included and analyzed corresponding to 1 cohort of 3 patients per dose. Data shown is a summary of the relative change of asparagine (%) from baseline over time (analysis set) | Posted | Mean | Standard Deviation | UI/Kg | Days 0, 1, 3, 7, 14, 21, 28, 35, 42, 56 |
|
|
|
| Secondary | Number of Patient Positive for Anti-L-asparaginase Antibodies | Titers of E. coli anti-asparaginase antibodies evaluated over time to assess immunogenicity | Summary of anti-L-asparaginase antibodies over time by number of patients | Posted | Count of Participants | Participants | No | Day 0, 1, 28 and 56 |
|
|
|
| Secondary | Summary of CEA Level Over Time | Assess tumor response, evaluated by carcinoembryonic antigen (CEA) tumor marker evolution | Sample collection not completed at each timepoint for each patient. All data available presented below. | Posted | Median | Full Range | ng/ml | Day 0, 28, 56 |
|
|
|
| Secondary | Summary of CA 19.9 Over Time | Tumor response Evaluation by cancer antigen (CA)19.9 evolution over time | Sample collection not completed at each timepoint for each patient. All data available presented below. | Posted | Median | Full Range | u/ml | Day 0, 28 and 56 |
|
|
|
| 1 |
| 3 |
| 3 |
| 3 |
| 3 |
| 3 |
| EG001 | GRASPA 50 | 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 3 subjects enrolled; 3 subjects completed | 0 | 3 | 0 | 3 | 3 | 3 |
| EG002 | GRASPA 100 | 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 3 subjects enrolled; 1 subject completed | 1 | 3 | 0 | 3 | 2 | 3 |
| EG003 | GRASPA 150 | 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 3 subjects enrolled; 0 subjects completed | 1 | 3 | 0 | 3 | 2 | 3 |
| Increase of Lumbar Pain | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Systematic Assessment |
|
| Increase of Abdominal Pain | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
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| Diarrohea | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
|
| Gastroesophageal reflux | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
|
| Tongue disorder | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (14.0) | Systematic Assessment |
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| Astenia | General disorders | MedDRA (14.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (14.0) | Systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA (14.0) | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA (14.0) | Systematic Assessment |
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| ECOG Performance Status worsened | Investigations | MedDRA (14.0) | Systematic Assessment |
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| Antithrombin III decreased | Investigations | MedDRA (14.0) | Systematic Assessment |
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| Weight decreased | Investigations | MedDRA (14.0) | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Systematic Assessment |
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| Muscle spasm | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (14.0) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (14.0) | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA (14.0) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (14.0) | Systematic Assessment |
|
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| D004066 |
| Digestive System Diseases |
| D010182 | Pancreatic Diseases |
| D004700 | Endocrine System Diseases |
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