A Look at Acalabrutinib Clinical Trials

Advances in medicine over the past 10 years have revolutionized care for patients with chronic lymphocytic leukemia (CLL).^1,2 One such advance has been the use of medications called Bruton tyrosine kinase (BTK) inhibitors, which have rapidly become the standard of care for many patients.^1,2 Ibrutinib was the first BTK inhibitor approved for use in CLL, although newer BTK inhibitors have been developed, such as acalabrutinib, that offer similar efficacy as ibrutinib, but with greater selectivity intended to decrease safety concerns such as bleeding and atrial fibrillation.^2,3

First approved in 2017 for treating mantle-cell lymphoma (MCL), acalabrutinib has been approved for the treatment of adults with CLL and small lymphocytic lymphoma (SLL) in the United States since November 2019.^4-6 Acalabrutinib has been shown to be effective and is approved for use as either a single agent (as monotherapy) or when combined with the immune system–modulating drug obinutuzumab.⁴ Several other US clinical trials are currently underway to investigate the use of acalabrutinib in combination with other medications for both CLL and other blood cancers.

One such study (NCT03836261) is evaluating the efficacy and safety of acalabrutinib in combination with another CLL drug, venetoclax, both with and without the addition of obinutuzumab in patients with previously untreated CLL.⁷ This phase 3 study is currently recruiting approximately 780 adult subjects around the country who are in relatively good health (ie, capable of caring for themselves and are generally fit enough to be up and about for more than half of their waking hours).⁷ Subjects included in this study must have active CLL that requires treatment, and their disease cannot have the gene mutations known as del(17p) or TP53.⁷ All subjects will receive CLL treatment, and will be randomized to receive either acalabrutinib and venetoclax; acalabrutinib, venetoclax, and obinutuzumab; or chemoimmunotherapy.⁷ Scheduled to complete in 2024, the key measurement made in this study will be how many patients in each of the 3 groups are treated without disease progression.⁷

A similar, smaller study (NCT03580928) is also evaluating acalabrutinib in combination with venetoclax and obinutuzumab for patients with untreated CLL, but this study has a different objective.⁸ Rather than focusing on how long patients are treated without disease progression, the primary goal of this phase 2 study is to measure how many patients achieve a “complete response,” meaning that investigators cannot detect any signs of CLL using computed tomography scans, bone marrow biopsy, or a sensitive test called minimal residual disease testing.⁸ Led by investigators at the Dana-Farber Cancer Institute in Boston, this study is currently recruiting approximately 72 subjects at 5 sites in New England.⁸ To be eligible, subjects must have active CLL or SLL that requires treatment, they must be in relatively good health, and they must meet certain requirements regarding liver and kidney function as well as certain blood parameters.⁸ Notably, and different from the previously mentioned study, subjects in this study may be eligible if they have gene mutations del(17p) or TP53.⁸

Another combination, acalabrutinib plus rituximab, is being evaluated to determine whether it can decrease the amount of time required to achieve a complete response and perhaps allow for shorter, less toxic therapy (NCT03788291).⁹ Rituximab is related to obinutuzumab as they are both anti-CD20 monoclonal antibodies, a class of drugs that can modulate the body’s immune system.^10,11 However, unlike obinutuzumab, which must be administered intravenously, rituximab is also available as a subcutaneous injection, and investigators of this study hypothesize that frequent dosing with low doses of subcutaneous rituximab may further increase the efficacy of acalabrutinib in previously untreated patients with CLL or SLL.⁹ This phase 2 study, led by researchers at the University of Rochester, seeks to recruit approximately 40 subjects in relatively good health with active CLL or SLL that requires treatment.⁹

Looking at other blood cancers, acalabrutinib is currently being evaluated in combination with another relatively novel cancer treatment, pembrolizumab, in a phase 1b/2 study (NCT02362035).¹² Pembrolizumab belongs to a class of drugs called immunotherapies, which help the patient’s own immune system to fight cancer.¹³ This study is already ongoing, having recruited approximately 160 subjects with CLL, SLL, MCL, follicular lymphoma, multiple myeloma, and many other blood cancers at sites around the United States.¹³ Being an early-phase trial, this study is primarily concerned with safety of the acalabrutinib + pembrolizumab combination, although preliminary efficacy data can also be expected when this study concludes in 2025.¹³

Acalabrutinib is also being investigated with another novel molecule known as ACP-319. Similar to acalabrutinib, ACP-319 inhibits signals within lymphomas, such as CLL, to prevent their growth.¹⁴ In 2 separate, ongoing clinical trials, a regimen of acalabrutinib in combination with ACP-319 is being evaluated in patients with non-Hodgkin lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia (NCT02328014) and CLL (NCT02157324).^15,16 Both studies are being conducted at various sites around the United States, with a total of 50 subjects having been recruited.^15,16 The primary goal of both studies is to evaluate the safety of the drug combination, although both have been designed to provide preliminary efficacy information when they complete in 2025.^15,16

Together, these studies and others are poised to further expand the role of acalabrutinib in treating CLL, and to potentially validate its use in other blood cancers. Just as the past decade was revolutionary with regard to treatment options, the future holds just as much promise for patients with CLL.

Interested individuals can learn about all acalabrutinib studies at ClinicalTrials.gov, and patients who would like to participate in a clinical trial should discuss their options with their healthcare team.

References

1. Timofeeva N, Gandhi V. Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. Blood Cancer J. 2021;11:79.
2. Isaac K, Mato AR. Acalabrutinib and its therapeutic potential in the treatment of chronic lymphocytic leukemia: a short review on emerging data. Cancer Manag Res. 2020;12:2079-2085.
3. AstraZeneca. AZD1222 US phase III trial met primary efficacy endpoint in preventing COVID-19 at interim analysis. Published March 22, 2021. www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-us-vaccine-trial-met-primary-endpoint.html. Accessed May 24, 2021.
4. Calquence (acalabrutinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
5. US Food and Drug Administration (FDA). FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. Published October 31, 2017. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma. Accessed May 20, 2021.
6. US Food and Drug Administration (FDA). Project Orbis: FDA approves acalabrutinib for CLL and SLL. Published November 21, 2019. www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll. Accessed May 21, 2021.
7. ClinicalTrials.gov. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. https://clinicaltrials.gov/ct2/show/NCT03836261. Accessed May 24, 2021.
8. ClinicalTrials.gov. Acalabrutinib, venetoclax, and obinutuzumab for initial therapy of CLL (AVO). https://clinicaltrials.gov/ct2/show/NCT03580928. Accessed May 24, 2021.
9. ClinicalTrials.gov. Acalabrutinib and high frequency low dose subcutaneous rituximab in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma. https://clinicaltrials.gov/ct2/show/NCT03788291. Accessed May 24, 2021.
10. Rituxan Hycela (rituximab and hyaluronidase human) [prescribing information]. South San Francisco, CA: Genentech Inc; 2021.
11. Gazyva (obinutuzumab) [prescribing information]. South San Francisco, CA: Genentech Inc; 2021.
12. ClinicalTrials.gov. ACP-196 (Acalabrutinib) in combination with pembrolizumab, for treatment of hematologic malignancies (KEYNOTE145). https://clinicaltrials.gov/ct2/show/NCT02362035. Accessed May 24, 2021.
13. Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck, Sharpe, and Dohme Corp; 2021.
14. Spriano F, Tarantelli C, Gaudio E, et al. Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 in pre-clinical models of aggressive lymphomas. Br J Haematol. 2019;187:595-601.
15. ClinicalTrials.gov. Acalabrutinib (ACP-196) in combination with ACP-319, for treatment of B-cell malignancies. https://clinicaltrials.gov/ct2/show/NCT02328014. Accessed May 24, 2021.
16. ClinicalTrials.gov. Acalabrutinib in combination with ACP-319, for treatment of chronic lymphocytic leukemia. https://clinicaltrials.gov/ct2/show/NCT02157324. Accessed May 24, 2021.