Phase I study of single-agent CC-292, a highly selective Brutons tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia

Brown, Jennifer R.; Harb, Wael A.; Hill, Brian T.; Gabrilove, Janice; Sharman, Jeff P.; Schreeder, Marshall T.; Barr, Paul M.; Foran, James M.; Miller, Thomas P.; Burger, Jan A.; Kelly, Kevin R.; Mahadevan, Daruka; Ma, Shuo; Li, Yan; Pierce, Daniel W.; Barnett, Evelyn; Marine, Jeffrey; Miranda, M.A.M.P.; Azaryan, Ada; Yu, Xinmin; Nava‐Parada, Pilar; Mei, Jay; Kipps, Thomas J.

doi:10.3324/haematol.2015.140806

Cited by 62 publications

(42 citation statements)

References 13 publications

(18 reference statements)

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“…(28) The apparently inferior clinical activity of an earlier highly selective BTK inhibitor, spebrutinib (CC-292, AVL-292), raised the question whether inhibition of kinases other than BTK are, in part, responsible for ibrutinib’s anti-tumor efficacy. (35, 36) Here, we report that acalabrutinib is as potent as ibrutinib at inhibiting BTK and pathways downstream, utilizing in vitro and ex vivo assays. Further, acalabrutinib showed potent in vivo activity in two complementary mouse models representing the disease spectrum of primary CLL in the xenograft model and a more aggressive disease in the transgenic mouse model.…”

Section: Discussionmentioning

confidence: 92%

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Herman

Montraveta

Niemann

et al. 2017

Clinical Cancer Research

134

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Purpose Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Experimental Design Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water. Results Utilizing biochemical assays we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared to ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects including decreased phosphorylation of PLCγ2, ERK and significant inhibition of CLL cell proliferation. Further, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared to vehicle treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2 and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared to mice receiving vehicle. Conclusions Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6 and ERK). In two complementary mouse models of CLL acalabrutinib significantly reduced tumor burden and increased survival compared to vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared to ibrutinib while demonstrating significant anti-tumor efficacy in vivo on par with ibrutinib.

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Section: Discussionmentioning

confidence: 92%

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Herman

Montraveta

Niemann

et al. 2017

Clinical Cancer Research

134

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“…CC-292 was well tolerated, but demonstrated inferior clinical results compared with ibrutinib. 24,25 At the time, it was suggested CC-292 maybe a more selective inhibitor of Btk than ibrutinib. This introduced the question do irreversible Btk inhibitors need to inhibit alternative targets, as ibrutinib does, to ensure efficacy?…”

Section: Discussionmentioning

confidence: 99%

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

Harrington²,

et al. 2016

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Background Irreversible inhibition of Bruton tyrosine kinase (Btk) by ibrutinib represents a significant therapeutic advance for chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromise its therapeutic index. Acalabrutinib (ACP-196) is a more selective irreversible Btk inhibitor specifically designed to improve upon the safety and efficacy of first generation Btk inhibitors. Methods Sixty-one patients with relapsed CLL were treated in a phase 1–2 multicenter study designed to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral acalabrutinib. Patients were continuously treated with acalabrutinib 100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the expansion portion. Results Patient demographics include a median age of 62 years; median of 3 prior therapies; 31% del(17)(p13.1) and 75% unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxicities occurred. The most common adverse events observed were headache (43%), diarrhea (39%) and increased weight (26%). Most adverse events were Grade 1–2. At a median follow-up of 14.3 months, the best overall response rate was 95%, including 85% partial response, 10% partial response with lymphocytosis and 5% stable disease. In patients with del(17)(p13.1), the best overall response was 100%. No cases of Richter’s transformation and only 1 CLL progression have occurred. Conclusions Acalabrutinib is a highly selective Btk inhibitor that provides effective and well tolerated treatment for patients with relapsed CLL, including those with del(17)(p13.1).

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“…1 Finally, the impressive clinical results with small molecules that target kinases in the BCR pathway further support the importance of this pathway. In particular, inhibitors of LYN (dasatinib), 13 SYK (fostamatinib), 14 PI3Kd (idelalisib), 15,16 and BTK (ibrutinib, CC-292) [17][18][19][20] have shown marked antitumor effects in clinical trials. BTK, a member of the Tec family of kinases, couples BCR activation to intracellular calcium release and NF-kB signaling.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL

Herman

Mustafa

Gyamfi

et al. 2014

Blood

219

197

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• Ibrutinib inhibits both BCR and NF-kB signaling in lymph node and bone marrow resident CLL cells.• Rapid and sustained reduction of cellular activation and tumor proliferation was achieved in all anatomic compartments.Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-kB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in the blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway-specific gene signatures, we detected a rapid and sustained downregulation of BCR and NF-kB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment. Ibrutinib reduced phosphorylation of PLCg2 and ERK and decreased nuclear protein expression of NF-kB p50. Ibrutinib significantly decreased tumor proliferation and expression of surface activation markers CD69 and CD86, independent of prognostic factors such as IGHV mutational status, chromosome 17p deletion, or prior treatment history. Interestingly, stronger inhibition of BCR signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2. Together, these data validate on-target effects of BTK inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo. This study is registered at www.clinicaltrials.gov as #NCT01500733. (Blood. 2014;123(21):3286-3295)

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Phase I study of single-agent CC-292, a highly selective Brutons tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia

Cited by 62 publications

References 13 publications

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL

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