Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia
- Registration Number
- NCT01523782
- Lead Sponsor
- ERYtech Pharma
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 30
- 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
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description GRASPA 50 IU/kg GRASPA 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. GRASPA 100 IU/kg GRASPA 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 GRASPA 150 IU/kg GRASPA 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
- Primary Outcome Measures
Name Time Method Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment 7 days after the first administration of GRASPA® during Induction 1 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®
Safety Endpoint - DLTs Assessed During Induction 1 and Induction 2 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.
- Secondary Outcome Measures
Name Time Method Cerebral Spinal Fluid Concentrations of Glutamic Acid Induction 1 and Induction 2 Mean cerebral spinal fluid glutamic acid concentration
Number of Patients Positive for Anti-L-asparaginase Antibodies Induction 1 and Induction 2 Evaluation of the number of patients testing positive for anti-asparaginase antibodies.
Number of Participants With Complete Remission (CR) Rate Following Induction 1 and Induction 2 1 and 2 months 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%Cerebral Spinal Fluid Concentrations of Glutamine Induction 1 and Induction 2 Mean cerebral spinal fluid glutamine concentration
Summary of Free Asparaginase Over Time Induction 1 and Induction 2 Summary of Encapsulated Asparaginase (U/L) Over Time Induction 1 and Induction 2 Cerebral Spinal Fluid Concentrations of Aspartic Acid Induction 1 and Induction 2 Mean cerebral spinal fluid aspartic acid concentration
Plasma Concentrations of Asparagine Induction 1 & Induction 2 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.
Plasma Concentrations of Glutamine Induction 1 and Induction 2 Mean glutamine concentration over time.
Plasma Concentrations of Glutamic Acid. Induction 1 and Induction 2 Mean glutamic acid concentration over time.
Cerebral Spinal Fluid Concentrations of Asparagine Induction 1 and Induction 2 Mean cerebral spinal fluid asparagine concentration over time.
Plasma Concentrations of Aspartic Acid Induction 1 and Induction 2 Mean plasma concentration of aspartic acid over time.