Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The main purpose of this study is to determine the maximum tolerated and efficient dose of GRASPA® in combination with polychemotherapy treatment of elderly patients with ALL, 55 years and over, Philadelphia chromosome-negative (ALL Ph-).

Detailed Description
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This open label, non randomised, multicentric and national phase IIa study was designed to evaluate the safety and efficacy of GRASPA®, a suspension of red blood cells encapsulating E. Coli L-asparaginase, at different doses and in combination with the polychemotherapy regimen recommended by the European Working Group on Adult ALL (EWALL) for frontline therapy of patients with ALL Ph-, aged 55 years old and over. Patients with a good performance status (WHO score ≤2) and a newly diagnosed ALL Ph- were treated with the backbone polychemotherapy consisting of a first 4-week induction phase comprising dexamethasone, vincristine and idarubicin, a second 4-week induction phase including cyclophosphamide, cytarabine, a 6-month consolidation phase consisting of 6 alternating cycles with methotrexate, asparaginase and folinic acid (cycles 1, 3 and 5) and high-dose cytarabine (cycles 2, 4 and 6) with Granulocyte colony stimulating factor (G-CSF) support followed by a 16-month maintenance period with mercaptopurine, methotrexate and vincristine/dexamethasone pulses. GRASPA® was administered on day 3 of induction 1 and on day 6 of induction 2 of the chemotherapy regimen.

Official Title
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An Escalating Dose Phase IIa Study of L-Asparaginase Encapsulated in Erythrocytes (GRASPA®) in Association With Polychemotherapy During Induction Phase for Treatment of Elderly Patients With Acute Lymphoblastic Leukaemia (ALL), Aged 55 Years and Over, With Philadelphia Chromosome-negative (ALL Ph-)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: GRASPA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged ≥55 years old With newly diagnosed ALL without prior treatment Capable to receive polychemotherapy (World Health Organization (WHO) performance status ≤2) With or without meningeal disease Having signed an Informed Consent Form Subscribed to social security insurance Exclusion Criteria: ALL translocation(9;22) and/or BCR-ABL (Breakpoint Cluster Region-Abelson) positive Performance status incompatible with chemotherapy treatment (WHO score >2) Patient presenting with a general or visceral contraindication to intensive treatment including : Cardiac insufficiency defined as Left Ventricular Ejection Fraction <50% of the theoretical value Plasma creatinine concentration 2 times greater than the upper limit of laboratory ranges, except if related to ALL Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) levels 5 times greater than the upper limit of laboratory ranges, except if related to ALL Patient with another evolutive cancer other than ALL Severe evolutive infection, or Human Immunodeficiency Virus (HIV) seropositive or, active hepatitis related to B or C viral infection Prior treatment with L-asparaginase (irrespective of the form) History of grade 3 transfusional incident (life threatening) Patient presenting rare and/or dangerous anti-erythrocyte antibodies thus leading to the unavailability of phenotype compatible Red Blood Cells Concentrate Patient included in another clinical trial during the last 4 weeks

Ages Eligible for Study
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Minimum Age: 55 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 50 IU/kg<br>Each patient will receive GRASPA 50 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase. | Drug: GRASPA<br>* Each patient will receive GRASPA at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase<br>|
| Experimental: GRASPA 100 IU/kg<br>Each patient will receive GRASPA 100 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase | Drug: GRASPA<br>* Each patient will receive GRASPA at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase<br>|
| Experimental: GRASPA 150 IU/kg<br>Each patient will receive GRASPA 150 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase | Drug: GRASPA<br>* Each patient will receive GRASPA at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment | The main evaluation criterion is a composite efficacy/toxicity criterion. Efficacy, assessed during induction 1: percentage of patients responding to treatment, i.e. with plasma Asn concentration ≤2µM (depleted), for a duration of at least 7 days after the administration of GRASPA® | 7 days after the first administration of GRASPA® during Induction 1 | 
| Safety Endpoint - DLTs Assessed During Induction 1 and Induction 2 | Safety: Toxicity, assessed during Induction 1 and Induction 2: according to NCI-CTCAE v3.0 August 2006, with Dose Limiting Toxicities (DLT) defined as: Grade 2 to 4 pancreatic toxicity, Grade 3 or 4 hepatic toxicity, allergic toxicity or deep cerebral thrombosis, known as potentially related to L-asparaginase; hematological toxicity defined as bone marrow blast free aplasia, 30 days following the last injection of chemotherapy, all other Grade 4 toxicities. | Induction 1 and Induction 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Asparagine | Mean plasma concentration of asparagine over time. Participants who were Below the Lower Limit of Quantification (BLLQ) were assigned a value of 0.51 μmol/L. | Induction 1 & Induction 2 | 
| Plasma Concentrations of Aspartic Acid | Mean plasma concentration of aspartic acid over time. | Induction 1 and Induction 2 | 
| Plasma Concentrations of Glutamine | Mean glutamine concentration over time. | Induction 1 and Induction 2 | 
| Plasma Concentrations of Glutamic Acid. | Mean glutamic acid concentration over time. | Induction 1 and Induction 2 | 
| Cerebral Spinal Fluid Concentrations of Asparagine | Mean cerebral spinal fluid asparagine concentration over time. | Induction 1 and Induction 2 | 
| Cerebral Spinal Fluid Concentrations of Aspartic Acid | Mean cerebral spinal fluid aspartic acid concentration | Induction 1 and Induction 2 | 
| Cerebral Spinal Fluid Concentrations of Glutamine | Mean cerebral spinal fluid glutamine concentration | Induction 1 and Induction 2 | 
| Cerebral Spinal Fluid Concentrations of Glutamic Acid | Mean cerebral spinal fluid glutamic acid concentration | Induction 1 and Induction 2 | 
| Summary of Free Asparaginase Over Time |  | Induction 1 and Induction 2 | 
| Summary of Encapsulated Asparaginase (U/L) Over Time |  | Induction 1 and Induction 2 | 
| Number of Patients Positive for Anti-L-asparaginase Antibodies | Evaluation of the number of patients testing positive for anti-asparaginase antibodies. | Induction 1 and Induction 2 | 
| Number of Participants With Complete Remission (CR) Rate Following Induction 1 and Induction 2 | CR was defined using: Clinical criteria: disappearance of clinical signs of acute lymphocytic leukemia (ALL) Blood criteria: neutrophils > 1 G/L and platelets >100 G/L Medullary criteria: normally rich bone marrow and percentage of blasts <5% | 1 and 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic leukemia, Elderly patient, Asparaginase