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FDA Grants Acalabrutinib Breakthrough Designation in MCL

The FDA has granted acalabrutinib a breakthrough therapy designation for patients with previously-treated mantle cell lymphoma.

The FDA has granted acalabrutinib a breakthrough therapy designation for patients with previously-treated mantle cell lymphoma (MCL), according to AstraZeneca, the manufacturer of the highly selective, potent BTK inhibitor.

The breakthrough designation, which will expedite the development and review of acalabrutinib in MCL, is based on the totality of clinical data from the acalabrutinib development program, including results from the phase II ACE-LY-004 clinical trial in patients with relapsed/refractory MCL. In its press release on the FDA action, AstraZeneca did not include any results or indicate when specific data for acalabrutinib in MCL would be made available.

Acerta Pharma, AstraZeneca’s hematology research and development center of excellence, developed acalabrutinib to treat multiple B-cell cancers. The acalabrutinib development program includes both monotherapy and combination therapy strategies in chronic lymphocytic leukemia (CLL), MCL, Waldenström macroglobulinemia, follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma, as well as monotherapy and combination trials in solid tumors.

“This is an exciting regulatory milestone for our work in hematology,” Flavia Borellini, PhD, Acerta Pharma CEO, said in a press release. “Acalabrutinib is a potent, irreversible BTK inhibitor with a high degree of specificity for its target. If approved, it could be a clinically meaningful treatment option for patients with this devastating disease.”

MCL is an aggressive B-cell non-Hodgkin lymphoma with a poor prognosis. The disease accounts for up to 6% of new non-Hodgkin lymphoma cases in Western countries each year, with an annual incidence of 0.5 per 100,000 persons and an estimated prevalence of 3.5 per 100,000.

“New treatments are urgently needed for people with mantle cell lymphoma who relapse or do not respond to current therapy,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a press release. “Breakthrough therapy designation for acalabrutinib will help us bring this potential new medicine to appropriate patients as quickly as possible.”

Patients with advanced MCL have seen an increase in treatment options in recent years. In 2013, the FDA approved ibrutinib (Imbruvica) for patients with MCL who have received at least 1 prior therapy, and lenalidomide (Revlimid) for patients who have relapsed or whose disease has progressed after 2 prior therapies, including at least 1 prior treatment with bortezomib (Velcade).

Bortezomib was approved for patients with previously treated MCL in 2006 and for treatment-naïve patients in 2014.

Available data for acalabrutinib have demonstrated promising activity in patients with CLL and small lymphocytic leukemia (SLL). Results from the phase I/II ACE-CL-001 trial presented at the 2016 ASH Annual Meeting showed that the overall response rate (ORR) was 79% with acalabrutinib in patients with ibrutinib-intolerant CLL/SLL.1

Of 29 patients evaluable for response, best response was a complete response (CR) in 1 patient (3.4%), a partial response (PR) in 15 (51.7%), PR with lymphocytosis (PRL) in 7 (24.1%), and stable disease (SD) in 6 (20.7%). The ORR when including only CR plus PR was 55.2%, and was 79.3% when including PRL in the ORR definition. All evaluable patients achieved at least SD. The median time to PRL or better was 1.9 months.

In a separate abstract presented at the 2016 ASH Annual Meeting, acalabrutinib demonstrated an ORR of 38.1% in a cohort of patients with Richter transformation from the same ACE-CL-001 trial.2


  1. Awan FT, Schuh A, MD PhD, Brown JR, et al. Acalabrutinib monotherapy in patients with ibrutinib intolerance: Results from the phase 1/2 ACE-CL-001 clinical study. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 638.
  2. Hillmen P, Schuh A, Eyre TA, et al. Acalabrutinib Monotherapy in Patients with Richter Transformation from the Phase 1/2 ACE-CL-001 Clinical Study. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 60.