Regulatory Decision Summary for Blincyto

There are no effective treatment options for pediatric patients with relapsed or refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Blincyto represents a promising therapy for these patients, targeting CD-19 on B-cells and CD-3 on polyclonal T-cells resulting in T-cell induced perforin/granzyme-mediated lysis of malignant B-cells. Promising evidence of efficacy for Blincyto was described previously in adults with relapsed or refractory disease, which led to issuance of a Notice of Compliance in December of 2015, as per the Notice of Compliance with Conditions (NOC/c) Guidance. In this Supplemental New Drug Submission (SNDS), a complete remission rate of 38.6% (27/70) was reported in the Phase I/II Study MT103-205 for pediatric patients treated with Blincyto who had relapsed or refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. The median relapse-free survival was 4.4 months. The remission rate and durations of response occurred in the background of a large overall tumour burden (approximately 75% of pediatric acute lymphoblastic leukemia patients had greater than 50% bone marrow blasts at enrollment). These results were considered promising evidence of efficacy for Blincyto in the treatment of pediatric patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The sponsor commits to providing the final study report from the Childrens Oncology Group Phase III Study AALL1331 in order to verify the clinical benefit of Blincyto in these pediatric patients. This will be a group-wide risk-stratified, randomized Phase III study to test whether incorporation of Blincyto into the treatment of patients with childhood B-Lymphoblastic Leukemia (B-ALL) at first relapse will improve disease free survival.

The overall safety profile of Blincyto in the Phase I/II study MT103-205 was acceptable for pediatric patients with refractory or relapsed acute lymphoblastic leukemia. In general, adverse reactions reported in pediatrics treated with Blincyto were similar in type and severity to those documented in the approved adult indication and no new safety findings were identified. The Product Monograph was updated in this Supplemental New Drug Submission so all patients ≥ 45 kilograms would receive the currently approved Blincyto fixed dosing regimen (9/28 µg/day), regardless of the age of the patient. The rationale for this update was that pharmacokinetic results suggested that body size was not a sensitive factor affecting blinatumomab clearance, indicating that pediatric and adult patients should have comparable exposure to blinatumomab when receiving the fixed dosing regimen. Forty-five kilograms was chosen as the cut-off since this approximates the smallest patient who received Blincyto in the approved adult Phase II study. At the same time, because inadvertent administration of the fixed Blincyto dose to very small pediatric patients may not be well tolerated, the Product Monograph was also updated with a statement in the Warnings and Precautions section (under General, Medication Errors) that patients <45 kilograms must be treated with a Blincyto dose based on body surface area (5/15 µg/m²/day). This warning is to remind prescribers to dose the small and lighter pediatric patients appropriately so as to avoid unnecessary serious adverse reactions in an already fragile patient population.

Overall, the results of the Phase I/II MT103-205 study support the promising evidence of efficacy with established safety for Blincyto in the treatment of pediatric patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

The submission was issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance.