Wojciech Jurczak, Nagah Elmusharaf, Christopher P Fox, William Townsend, Amanda G Paulovich, Jeffrey R Whiteaker, Fanny Krantz, Chuan-Chuan Wun, Graeme Parr, Shringi Sharma, Veerendra Munugalavadla, Richa Manwani, Emma Dean, Talha Munir
{"title":"ceralasertib单药或与acalabrutinib联合治疗高风险复发/难治性慢性淋巴细胞白血病的I/II期结果","authors":"Wojciech Jurczak, Nagah Elmusharaf, Christopher P Fox, William Townsend, Amanda G Paulovich, Jeffrey R Whiteaker, Fanny Krantz, Chuan-Chuan Wun, Graeme Parr, Shringi Sharma, Veerendra Munugalavadla, Richa Manwani, Emma Dean, Talha Munir","doi":"10.1177/20406207231173489","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in <i>TP53</i>- and <i>ATM</i>-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.</p><p><strong>Objectives: </strong>To evaluate ceralasertib ± acalabrutinib in R/R CLL.</p><p><strong>Design: </strong>Nonrandomized, open-label phase I/II study.</p><p><strong>Methods: </strong>In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.</p><p><strong>Results: </strong>Eleven patients were treated [arm A, <i>n</i> = 8 (cohort 1, <i>n</i> = 5; cohort 2, <i>n</i> = 3); arm B, <i>n</i> = 3 (acalabrutinib plus ceralasertib, <i>n</i> = 2; acalabrutinib only, <i>n</i> = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached.</p><p><strong>Conclusion: </strong>Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size.</p><p><strong>Registration: </strong>NCT03328273.</p>","PeriodicalId":23048,"journal":{"name":"Therapeutic Advances in Hematology","volume":null,"pages":null},"PeriodicalIF":3.4000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dd/f3/10.1177_20406207231173489.PMC10233611.pdf","citationCount":"0","resultStr":"{\"title\":\"Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.\",\"authors\":\"Wojciech Jurczak, Nagah Elmusharaf, Christopher P Fox, William Townsend, Amanda G Paulovich, Jeffrey R Whiteaker, Fanny Krantz, Chuan-Chuan Wun, Graeme Parr, Shringi Sharma, Veerendra Munugalavadla, Richa Manwani, Emma Dean, Talha Munir\",\"doi\":\"10.1177/20406207231173489\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in <i>TP53</i>- and <i>ATM</i>-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.</p><p><strong>Objectives: </strong>To evaluate ceralasertib ± acalabrutinib in R/R CLL.</p><p><strong>Design: </strong>Nonrandomized, open-label phase I/II study.</p><p><strong>Methods: </strong>In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.</p><p><strong>Results: </strong>Eleven patients were treated [arm A, <i>n</i> = 8 (cohort 1, <i>n</i> = 5; cohort 2, <i>n</i> = 3); arm B, <i>n</i> = 3 (acalabrutinib plus ceralasertib, <i>n</i> = 2; acalabrutinib only, <i>n</i> = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. 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Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.
Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.
Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL.
Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.
Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached.
Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size.
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Therapeutic Advances in Hematology delivers the highest quality peer-reviewed articles, reviews, and scholarly comment on pioneering efforts and innovative studies across all areas of hematology. The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in hematology, providing a forum in print and online for publishing the highest quality articles in this area.
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