FDA Approves Acalabrutinib Tablet Formulation in CLL/SLL and Relapsed/Refractory MCL

Acalabrutinib (Calquence) in tablet formulation has been approved by the FDA across all current indications for patients with chronic lymphocytic leukemia, small lymphocytic leukemia, and relapsed/refractory mantle cell lymphoma, according to a press release from AstraZeneca.¹

Results from the ELEVATE-PLUS trials, which comprised 3 phase 1 open-label, single-dose crossover studies, led to the approval. The tablet formulations was determined to be bioequivalent to capsules, conferring similar efficacy and safety profile expectations for the same dosing strength and schedule.

Acalabrutinib has previously been approved by the FDA in a capsule formulation.^2,3 With the capsule formulation of acalabrutinib, concomitant use of acid-reducing agents—such as proton pump inhibitors, antacids, and H2-receptor antagonists—leads to reduced acalabrutinib exposure and is not recommended. In addition, capsules may be hard for some patients to swallow, requiring alternative administration routes such as oral suspensions or nasogastric tubes. The new film-coated tablet (acalabrutinib maleate tablet) allows for immediate release and may be used in the aforementioned situations.

Acalabrutinib is a next-generation selective inhibitor of Bruton tyrosine kinase (BTK), that binds covalently and inhibits its activity. In B-cells, the BTK signaling leads to activation of pathways for B-cell proliferation, trafficking, chemotaxis, and adhesion.

“Patients with blood cancers like chronic lymphocytic leukemia and mantle cell lymphoma are often older and may face multiple medical conditions that may need intervention, including acid reflux or peptic ulcer disease. The US approval of acalabrutinib in a tablet form enables co-administration of the acalabrutinib tablet alongside a proton pump inhibitor. This provides another option for some patients with chronic lymphocytic leukemia and relapsed or refractory mantle cell lymphoma, enabling more patients to potentially benefit from this treatment,” John C. Byrd, MD, chair of the Department of Internal Medicine at the University of Cincinnati, said in the press release.

A total of 116 patients were enrolled in the ELEVATE-PLUS trials to assess the bioequivalence of acalaburtinib 100-mg tablets vs 100-mg capsules. Investigators studied proton pump inhibitor effects on acalabrutinib tablets vs the absence of proton pump inhibitor rabeprazole and how a high-fat diet compared with a fasting.

In December 2021, results from 66 patients in the ELEVATE-PLUS trial were presented at the American Society of Hematology Annual Meeting.⁴ Of note, tablets were administered in 14 patients to determine effects of presence vs absence of rabeprazole, in 16 to compared high-fat vs fasting diets, and in 20 to test administration of water suspension via nasogastric tube in the presence vs absence of rabeprazole. Investigators evaluated pharmacodynamics through BTK target occupancy in the peripheral blood mononuclear cells.

Bioequivalence of the active metabolite ACP-5862 was found between the tablets and capsules, with a geometric mean exposure of less than 5%. There were no clinical difference in acalabrutinib/ACP-5862 exposure when a proton pump inhibitor was added following tablet administration. Additionally, those on a high-fat diet did not experience any ills effects on exposure when treated with acalabrutinib tablets. Exposure to acalabrutinib/ACP-5862 was equivalent (<10% difference) for those in the maleate suspension group who had the drug delivered through a nasogastric tube vs the capsules.

Acalabrutinib tablets resulted in a favorable safety profile, with most adverse effects being mild and no serious cases being reported. Importantly, no new safety signals were noted.

References

1. Calquence tablet formulation approved in the US across current indications. News Release. AstraZeneca. August 5, 2022. Accessed August 5, 2022. https://bit.ly/3Q3i1eG
2. Project Orbis: FDA approves acalabrutinib for CLL and SLL. News Release. FDA. November 21, 2019. Accessed August 5, 2022. https://bit.ly/3P1vnGU
3. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News Release. FDA. October 31, 2017. Accessed August 5, 2022. https://bit.ly/3P4hnfD
4. Sharma S, Pepin X, Burri H, et al. New acalabrutinib formulation enables co-administration with proton pump inhibitors and dosing in patients unable to swallow capsules (ELEVATE-PLUS). Blood. 2021;138(suppl 1):4365. doi:10.1182/blood-2021-146610