ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

Sharman, Jeff P.; Banerji, Versha; Fogliatto, Laura; Herishanu, Yair; Munir, Talha; Walewska, Renata; Follows, George; Karlsson, Karin; Ghia, Paolo; Corbett, Gillian; Walker, Patricia; Egyed, Miklós; Jurczak, Wojciech; Salles, Gilles; Janssens, Ann; Cymbalista, Florence; Wierda, William G.; Coutre, Steven; Pagel, John M.; Skarbnik, Alan P; Kamdar, Manali; Woyach, Jennifer A.; Izumi, Raquel; Munugalavadla, Veerendra; Patel, Priti; Wang, Minhui; Wong, S. S.; Byrd, John C.

doi:10.1182/blood-2019-128404

Cited by 55 publications

(66 citation statements)

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“…21 Subsequent phase 3 trials, ELEVATE-TN and ASCEND, led to the FDA approval of acalabrutinib for treatment of CLL and SLL. 22,23 A treatment dose of 100 mg twice daily was considered the optimal dosage. At this dosing, acalabrutinib was demonstrated to bind to the C481 residue with evidence of complete BTK occupancy (99-100%) 4 hrs after dosing and 97% occupancy at 12 hrs post-dose.…”

Section: Development Of Acalabrutinibmentioning

confidence: 99%

“…27 Although the combination of acalabrutinib with an anti-CD20 monoclonal antibody has not been study in an in vivo model, several phase 2 and phase 3 studies are ongoing or have been completed that demonstrate the efficacy of acalabrutinib in combination with an anti-CD20 monoclonal antibody. 23,[28][29][30] Other acalabrutinib combinations have been studied in both in vitro and in vivo models. Acalabrutinib was combined with a PI3Kdelta inhibitor (ACP-319) in a murine CLL model and demonstrated greater reduction in tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 as compared to monotherapy.…”

Section: Preclinical Studies Of Acalabrutinib In Cllmentioning

confidence: 99%

“…In the phase 3 ELEVATE-TN study, patients with treatment naïve CLL requiring treatment were randomized in a 1:1:1 fashion to receive acalabrutinib alone or in combination with obinutuzumab or obinutuzumab plus chlorambucil. 23 A total of 535 patients was randomized with a median age of 70 years old (range, 41-91). The study included a significant proportion of high-risk or very high-risk patients based on CLL international prognostic index score (69% were high-risk, 12% were very high-risk).…”

Section: Acalabrutinib Combinationsmentioning

confidence: 99%

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<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

Isaac¹,

Mato²

2020

CMAR

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Recently, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed dramatically due to the development of drugs targeting proteins in the B cell antigen receptor (BCR) pathway. Acalabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, was recently FDA approved for treatment of treatment naïve and relapsed refractory CLL. Acalabrutinib was designed as a more selective BTK inhibitor as compared to ibrutinib in an attempt to mitigate some of the treatment limiting toxicities seen with ibrutinib such as atrial fibrillation and bleeding. In preclinical studies, acalabrutinib was demonstrated to have efficacy in CLL in both patient blood samples and murine models. A multinational phase 1/2 study demonstrated the efficacy and safety of acalabrutinib monotherapy in treatment naïve, relapsed refractory and ibrutinib-intolerant CLL patients. Subsequent phase 3 studies, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy or combination acalabrutinib and obinutuzumab to standard of care treatments and demonstrated acalabrutinib's improved efficacy and tolerability. Currently, a phase 3 study is ongoing to compare acalabrutinib to ibrutinib monotherapy (NCT02477696). In the setting of recent FDA approval, real-world evidence will help to elucidate the optimal use of acalabrutinib in the treatment of CLL.

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Section: Development Of Acalabrutinibmentioning

confidence: 99%

Section: Preclinical Studies Of Acalabrutinib In Cllmentioning

confidence: 99%

Section: Acalabrutinib Combinationsmentioning

confidence: 99%

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<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

Isaac¹,

Mato²

2020

CMAR

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“…Interim results from the Elevate-TN study estimates the 30-month progression-free survival to be 90% in the acalabrutinib + obinutuzumab arm, 82% with acalabrutinib as a single agent and 34% in the obinutuzumab and chlorambucil arm. 75 Acalabrutinib is now being compared head-to-head with ibrutinib in a phase 3 study (NCT02477696) ( Table 2). Combining targeted therapies with either other targeted therapies, chemotherapy or chemoimmunotherapy is appealing because of the possibility of achieving deeper and long-standing remissions.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

B cell signalling pathways—New targets for precision medicine in chronic lymphocytic leukaemia

2020

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The B cell receptor (BCR) is a master regulator of B cells, controlling cellular processes such as proliferation, migration and survival. Cell signalling downstream of the BCR is aberrantly activated in the B cell malignancy chronic lymphocytic leukaemia (CLL), supporting the pathophysiology of the disease. This insight has led to development and approval of small molecule inhibitors that target components of the BCR pathway. These advances have greatly improved the management of CLL, but the disease remains incurable. This may partly be explained by the inter-patient heterogeneity of the disease, also when it comes to treatment responses. Precision medicine is therefore required to optimize treatment and move towards a cure. Here, we discuss how the introduction of BCR signalling inhibitors has facilitated the development of functional in vitro assays to guide clinical treatment decisions on use of the same therapeutic agents in individual patients. The cellular responses to these agents can be analysed in high-throughput assays such as dynamic BH3 profiling, phospho flow experiments and drug sensitivity screens to identify predictive biomarkers. This progress exemplifies the positive synergy between basal and translational research needed to optimize patient care. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. How to cite this article: Skånland SS, Karlsen L, Taskén K. B cell signalling pathways-New targets for precision medicine in chronic lymphocytic leukaemia.

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“…При периоде наблюдения более 2 лет 79,3% пациентов, получавших акалабрутиниб, продолжат терапию препаратом. Частота таких нежелательных явлений, как ФП любой степени в группах акалабрутиниб в комбинации с обунутузумабом, акалабрутиниб в монотерапии и комбинации обинутузумаба с хлорамбуцилом составила 3, 4 и 1% соответственно, кровотечения любой степени/3-й степени: 43%/2%, 39%/2% и 12%/0%, и артериальная гипертензия выше 3-й степени: 3, 2 и 3% в 3 группах соответственно [13,14].…”

Section: участники экспертного советаunclassified

ELEVATE-TN Study. New data of acalabrutinib in first-line treatment of chronic lymphocytic leukemia. Resolution

et al. 2020

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Over the past decade, we have seen a significant change in modern approaches in the first-line treatment of chronic lymphocytic leukemia (CLL). The CLL-10 study data established the FCR regimen as the treatment of choice for younger patients with limited comorbidities, while for patients older than 65 years, the BR regimen is more often considered as less toxic one. According to published data, 46% of patients with newly diagnosed CLL have comorbidities. Moreover, high-risk patients with del(17p) and/or TP53 mutation do not have response on immunochemotherapy (ICT) most often. Thus, about 1/2 of the patients cannot be treated or will not respond to standard ICT regimens. Targeted therapy with Brutons tyrosine kinase (BTK) inhibitors is an important option of the first-line treatment of patients with CLL. Acalabrutinib is a highly selective second-generation BTK inhibitor that does not inhibit EGFR, ITK or TEC targets. Acalabrutinib in combination with obinutuzumab or as monotherapy can be considered as a highly effective and safe option of the first line of CLL therapy. Based on the hight selectivity of the agent, acalabrutinib can be considered as the preferable option for patients who are not eligible for ICT, including patients with commodities, such as cardiovascular diseases or risk factors for their development.

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ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

Cited by 55 publications

References 0 publications

<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

B cell signalling pathways—New targets for precision medicine in chronic lymphocytic leukaemia

ELEVATE-TN Study. New data of acalabrutinib in first-line treatment of chronic lymphocytic leukemia. Resolution

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