Phase I/II Clinical Trial of Erwinia Asparaginase (Erwinase^R) in Combination with Prednisolone, Vincristine and Pirarubicin in Children and Young Adults with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

Introduction: L-asparaginase is an important component of multi-agent chemotherapy for children and young adults with ALL. In Japan, only one asparaginase preparation, native-E-coli-asparaginase (Leunase^R), has been approved so far by the Health, Labour and Welfare Ministry. The incidence of clinical allergy to native-E-coli -asparaginase can be more than 30% with repeated administration. To continue treatment with asparaginase, Erwinia asparaginase (Erwinase^R), deriving from Erwinia chrysanthemi, is recommended for patients who develop clinical allergy to native-E-coli-asparaginase, because the drug has no cross reactivity. We planned phase I/II trial OP-01-001 to investigate the safety and efficacy of Erwinase in combination chemotherapy consist of prednisolone, vincristine and pirarubicin.

Patients and Methods: Eligible patients on this study were children and young adults with ALL/ LBL in remission, >=1 to =<25 years of age, and had developed allergy to E-coli-asparaginase. Patients with a history of pancreatitis or previous administration of Erwinase were excluded. The study was approved by IRB at each institution and patients/guardians provided informed consent/assent. In this trial regimen OP-01-001, level 1 (25,000) or level 0 (20,000 IU/m²) x 6 doses of Erwinase were planned to administer intramuscularly (IM) on day 2, 5, 7, 9, 11 and 13 with 40 mg/m²/day x15 days of prednisolone, 1.5mg/m² x 3 doses of vincristine and 20 mg/m²x 2 doses of pirarubicin. In phase I, we determined the maximum tolerated dose, dose limiting toxicity (DLT), and the recommended phase II dose (RP2D) of Erwinase. Safety, efficacy and pharmacokinetic/dynamic study were evaluated in all patients. Blood samples were obtained at scheduled time points during Erwinase therapy and assayed for asparaginase activity and asparagine concentration in plasma. Primary endpoint was asparaginase activity in plasma at 48h after the first dosing.

Results: A total of 24 eligible patients were enrolled to phase I/II study from February 2012 to January 2014. In phase I study, 6 eligible/evaluable patients were enrolled to level 1, starting at 25,000 IU/m². Since all patients completed the scheduled treatments without DLT in level 1, RP2D was determined 25,000 IU/m²and 18 patients were enrolled in phase II study.

PK, PD, safety and efficacy were evaluated as phase I/II study. The median age of 24 evaluated patients was 7.5 years (range 2-16) and 15 patients (62.5%) were male. In PK/PD study, one patient was excluded because essential clinical dataset was not obtained. After the first dosing, serum asparaginase activity exceeded 0.1 IU/mL in 23/23 patients (100%) at 48 hours and it did in 18/23 patients (78.3%) at 72 hours. After the sixth dosing, the activity at 72 hours was higher than 0.1 IU/mL in 19/23 (82.6%). Plasma asparagine was significantly depleted (<1.0 μM) in 22/23 (95.7%) 48 hours after the first dosing and it was also depleted in 22/23 (95.7%) 72 hours after the last dosing in all but one patients.

All patients maintained remission status during the trial. No allergic reaction related to Erwinase was reported. Hypertriglyceridemia or blood triglycerides increased was reported in 12/24 (50%), 4 cases in grade 3 and 1 in grade 4. Increase in blood sugar was observed in 3 patients (12.5%), 2 in grade 1 and 1 in grade 2. In addition, 23 (95.8%) and 1 (4.2%) developed decrease in fibrinogen and increase in ammonia at grade 2-4. Grade 3 febrile neutropenia and bacteremia were reported in 8 patients (33.3%) and in 1 patient (4.2%), respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death.

Conclusion: Erwinase as administered using the OP-01-001 regimen was well tolerated without unexpected toxicities and achieved good serum asparaginase activity at both 48 and 72 hours after dosing. In previous reports, a much lower dose of Erwinase at 10,000 IU/m²/dose was used in the study of EORTC (Duval M. Blood 2002;99:2734), which was subsequently assessed as suboptimal and the identical dose of erwinase at 25,000 IU/m²/dose was used in the study of COG (Salzer WL. Blood 2013;122:507). We herein showed that following allergy to E-coli native-asparaginase, erwinase 25,000 IU/m² x 6 doses IM in 2 or 3 days interval in 2 weeks was effective and safe in children and young adults in Japan.