Breakthrough Therapy Designation Granted to Blinatumomab for ALL

Sean E. Harper, MD

Sean E. Harper, MD

The FDA has granted a breakthrough therapy designation to blinatumomab for the treatment of adult patients with Philadelphia-negative relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), according to Amgen, the company developing the drug.

The breakthrough therapy designation was based on results from a phase II trial of 189 patients. As of January 2014, 43% (n = 82) of patients achieved a complete remission (CR) or CR with partial hematological recovery (CRh). These results were presented at the 2014 ASCO Annual Meeting and at the 19th Congress of the European Hematology Association.

"There is a high unmet need for new medicines to treat relapsed and refractory ALL patients, who have very few treatment options," Sean E. Harper, MD, executive vice president, Research and Development, Amgen, said in a statement. "The results from the phase II trial evaluating blinatumomab in adult patients with relapsed or refractory ALL are encouraging and provide a strong basis for a regulatory filing later this year and potential approval in this serious disease."

Blinatumomab is an investigational bispecific T-cell engager (BiTE) antibody engineered to direct cytotoxic T-cells to CD19- and CD3-expressing cells.

In the phase II trial, blinatumomab was given via continuous intravenous infusion on a four-weeks-on, two-weeks-off schedule for up to five cycles. The primary endpoint was CR or CRh within the first two cycles. Eighty percent of responses observed occurred in the first cycle.

Regardless of causality, as noted by the authors of the study, the most common adverse events reported were pyrexia (59%), headache (35%), and febrile neutropenia (29%). The most common ≥grade 3 adverse events observed were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Headache (4%), encephalopathy (3%), and ataxia (2%) were the most commonly reported ≥grade 3 nervous system disorders. In all, three patients experienced treatment-related grade 5 adverse events: sepsis (n = 2) and candida infection (n = 1).

In a single-arm, phase II trial that reported in 2012, 36 adult patients with relapsed or refractory B-precursor ALL were treated with a range of doses of blinatumomab. In that trial, 72% (n = 26) achieved a complete response or complete response with partial hematologic recovery. All but two patients achieved a molecular response on the trial, signifying no evidence of leukemic cells by polymerase chain reaction.

A phase III randomized, open-label study designed to evaluate the efficacy of blinatumomab versus investigator choice of SOC chemotherapy in patients with relapsed/refractory B-precursor ALL is currently recruiting patients.

In the study, patients will be randomized in a 2:1 ratio to receive blinatumomab or treatment with investigator’s choice of 1 of 4 protocol defined as standard of care chemotherapy regimens.

The study, known as the TOWER study, is estimated to enroll 400 patients and has an estimated completion date of July 2017. The primary endpoint of the study is overall survival.

BiTE antibodies are designed to engage endogenous T cells and avoid the need for ex vivo expansion or manipulation.

Blinatumomab is the first BiTE antibody in development and is also being investigated for the treatment of pediatric relapsed/refractory ALL, Philadelphia positive relapsed/refractory B-precursor ALL, minimal residual disease positive B-precursor ALL, and relapsed/refractory non-Hodgkin's lymphoma.

According to Amgen, over 6,000 cases of ALL were diagnosed in the U.S. in 2013 and the disease accounts for 12% of all leukemia.