Asparlas Drug Information

Acute Lymphoblastic Leukemia

ASPARLAS is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Study DFCI 11-001 The safety of ASPARLAS was investigated in Study DFCI 11-001, an open-label, randomized, active-controlled multicenter clinical trial that treated 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma, with ASPARLAS 2,500 U/m 2 (n=118) or pegaspargase 2,500 U/m 2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy. The median age on enrollment was 5 years (range, 1-20 years). The majority of patients were male (62%) and white (70%). Most patients were considered standard risk (SR, 59%) and had B-cell lineage ALL (87%). The median number of doses during the study was 11 doses for ASPARLAS (administered every three weeks) and 16 doses for pegaspargase (administered every two weeks). The median duration of exposure was 8 months for both ASPARLAS and pegaspargase.

There was 1 fatal adverse reaction (multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst). Table 2 summarizes the incidence of selected grades ≥3 adverse reactions that occurred in 2 or more patients receiving ASPARLAS. Because not all grade 1 and 2 adverse reactions were collected prospectively, only grade 3 and 4 adverse events are presented in Table 2. Table 2: Selected Grades ≥3 Adverse Reactions in Patients Receiving ASPARLAS with Multi-Agent Chemotherapy (Study DFCI 11-001) ASPARLAS or pegaspargase were administered as a component of multi-agent chemotherapy regimens. Adverse Reaction Grouped terms: Elevated transaminase : Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased; Bilirubin increased : Bilirubin conjugated increased, Blood bilirubin increased; Pancreatitis : Amylase increased, Lipase increased, Pancreatic necrosis, Pancreatitis, Pancreatitis relapsing; Abnormal clotting studies : Activated partial thromboplastin time prolonged, Blood fibrinogen decreased; Diarrhea : Colitis, Diarrhea, Enterocolitis, Neutropenic colitis; Hypersensitivity : Anaphylactic reaction, Drug hypersensitivity, Hypersensitivity; Embolic and thrombotic events SMQ : Device related thrombosis, Disseminated intravascular coagulation, Embolism, Intracardiac thrombus, Intracranial venous sinus thrombosis, Pulmonary embolism, Superior sagittal sinus thrombosis, Thrombosis in device, Venous thrombosis, Venous thrombosis limb; Sepsis : Bacterial sepsis, Sepsis; Dyspnea : Hypoxia, Respiratory failure; Hemorrhages SMQ (excludes laboratory terms): Disseminated intravascular coagulation, Epistaxis, Hematoma, Hemorrhage intracranial, Melena, Esophageal ulcer hemorrhage, Small intestinal hemorrhage, Upper gastrointestinal hemorrhage; Fungal infection : Fungal infection, Hepatic infection fungal, Respiratory tract infection fungal, Splenic infection fungal, Systemic candida; Pneumonia : Lung infection, Pneumonia, Pneumonitis; Arrhythmia : Atrioventricular block complete, Sinus tachycardia, Ventricular arrhythmia; Cardiac failure : Ejection fraction decreased, Left ventricular dysfunction. ASPARLAS 2,500 U/m 2 N=118 Pegaspargase 2,500 U/m 2 N=119 Grades ≥3 n (%) Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grades ≥3 n (%) Elevated transaminase 61 79 Bilirubin increased 24 30 Pancreatitis 21 29 Abnormal clotting studies 17 25 Diarrhea 10 6 Hypersensitivity 9 8 Embolic and thrombotic events 9 10 Sepsis 6 7 Dyspnea 5 1 Hemorrhages 5 5 Fungal infection 4 3 Pneumonia 4 8 Arrhythmia 2 1 Cardiac failure 2 1 In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the ASPARLAS arm was 98% (95/97), compared to 99% in the pegaspargase arm; the Kaplan-Meier estimates of overall survival of the treatment arms were comparable.

Study AALL07P4 The safety of ASPARLAS was also evaluated in Study AALL07P4, an open-label, randomized, active-controlled, multicenter clinical trial that treated patients with newly diagnosed high-risk B-precursor ALL using ASPARLAS 2,500 U/m 2 (n=43) or 2,100 U/m 2 (n=68), or pegaspargase 2,500 U/m 2 (n=52), as a component of an augmented Berlin-Frankfurt-Münster (BFM) therapy regimen. The median age was 11 years (range, 1-26 years); the median duration of exposure was 7 months for both ASPARLAS and pegaspargase. In this study, the induction mortality of patients treated with ASPARLAS was 2.8% (3 out of 111); there were no induction deaths among 52 patients treated with pegaspargase.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In Study DFCI 11-001, hypersensitivity reactions occurred in 80% of ASPARLAS-treated patients with new or an increased titer of anti-drug antibodies (ADA) and in 6% of those without ADA . Two patients with ADA experienced anaphylaxis .

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ASPARLAS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatic: Veno-occlusive disease

Pregnancy Risk Summary Based on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to a pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes.

Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring (see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 U/kg (0.2, 0.6 and 1 times the maximum recommended human dose, respectively, based on AUC) to pregnant rats during the period of organogenesis.

Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested. Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.

Pediatric Use The safety and effectiveness of ASPARLAS in the treatment of ALL have been established in pediatric patients 1 month to <17 years (no data for the age group <1 month old). Use of ASPARLAS in these age groups is supported by evidence from an adequate and well-controlled trial with additional safety from a second trial. The trials included 208 children with ALL or lymphoblastic lymphoma treated with ASPARLAS; there were 19 infants (1 month to <2 years old), 128 children (2 years to <12 years old), and 61 adolescents (12 years to <17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups .

is contraindicated in patients with: History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy History of serious pancreatitis during previous L-asparaginase therapy History of serious thrombosis during previous L-asparaginase therapy History of serious hemorrhagic events during previous L-asparaginase therapy Severe hepatic impairment History of serious hypersensitivity reactions to pegylated L-asparaginase. History of serious thrombosis during L-asparaginase therapy. History of serious pancreatitis related to previous L-asparaginase treatment.

History of serious hemorrhagic events during previous L-asparaginase therapy. Severe hepatic impairment.