Sean E. Harper, MD
The FDA has granted a priority review to an application to expand the approval of blinatumomab (Blincyto) to include the treatment of pediatric and adolescent patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The supplemental biologics license application (sBLA) was based on data from a single-arm phase I/II trial, known as study 205, which met its primary phase II endpoint of complete remission (CR) within the first 2 cycles of blinatumomab, according to Amgen, the manufacturer of the anti-CD19 immunotherapy.
The priority review program provides an expedited approval process for treatments that provide a substantial benefit over current options. The FDA is scheduled to make its final decision by September 1, 2016.
“Children and adolescents with ALL who experience a second or greater relapse or are refractory often have a dismal prognosis with survival rates below 10%,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a press release. “The FDA's acceptance of the sBLA submission for Blincyto reinforces immunotherapy as a potential option for children in need of new treatments to fight this complex disease and help prevent further relapse."
Study 205 is a multicenter, dose-finding, efficacy trial that accrued patients aged <18 years with Ph- B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplantation (HSCT). Following the phase I portion of the study, the recommended blinatumomab regimen proposed by an independent monitoring panel for phase II was stepwise dosing of 5/15-μg/m²/day.
All patients in the trial have completed therapy and are being observed for long-term outcomes. The data are being submitted for publication, Amgen reported.
The most common grade ≥3 adverse events (AEs) among patients receiving the recommended dose (n = 70) were anemia, thrombocytopenia, febrile neutropenia, hypokalemia, and neutropenia. Serious AEs were comparable to those previously reported for blinatumomab in adult patients.
Following a breakthrough therapy designation in July 2014, the FDA granted blinatumomab an accelerated approval for adult patients in this setting in December 2014, based on phase II data demonstrating strong clinical activity with the agent.
In the pivotal phase II study, the CR rate was 32.4% (95% CI, 25.7-39.7), the CR with partial hematological recovery (CRh) rate was 9.2% (95% CI, 5.4-14.3), and the combined CR/CRh rate was 41.6% (95% CI, 34.4-49.1). Overall, 80% of patients who achieved a CR also responded by minimum residual disease (MRD) testing. Approximately 39% of patients who achieved a CR/CRh went on to receive an HSCT.
The most common all-grade AEs were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). In all, 3 patients experienced treatment-related grade 5 AEs: sepsis (n = 2) and candida infection (n = 1).
Neurological side effects occurred in approximately 50% of patients. Additionally, 11% experienced cytokine release syndrome. To address these side effects, the FDA approved blinatumomab with a Boxed Warning and Risk Evaluation and Mitigation Strategy (REMS).
In February 2016, Amgen reported that the confirmatory phase III TOWER study was halted after an independent panel determined that blinatumomab improved overall survival (OS) versus standard chemotherapy in patients with Ph- relapsed/refractory B-cell precursor ALL.
The open-label phase III TOWER trial randomized patients in a 2:1 ratio to blinatumomab or investigator’s choice of 1 of 4 standard chemotherapy regimens. The primary endpoint was OS. Secondary endpoints included CR, duration of CR, patients achieving remission with MRD, and safety. The data from TOWER will be presented at an upcoming scientific meeting, according to Amgen.
Blinatumomab is a recombinant, single-chain monoclonal antibody that possesses antigen-recognition sites for CD3 and CD19. The CD3 complex consists of T cell surface glycoproteins, while CD19 is a tumor-associated antigen. The combination of these recognition sites into 1 therapy is thought to promote cytotoxic T lymphocyte and helper T lymphocyte activity against CD19-expressing B lymphocytes.