Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia
Background: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model.Methods: We conducted a phas...
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00369/full |
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| author | Prajwal Boddu Gautam Borthakur Mythili Koneru Xuelin Huang Kiran Naqvi William Wierda Prithviraj Bose Elias Jabbour Zeev Estrov Jan Burger Yesid Alvarado April Deshmukh Ami Patel Antonio Cavazos Lina Han Jorge E. Cortes Hagop Kantarjian Michael Andreeff Marina Konopleva |
| author_facet | Prajwal Boddu Gautam Borthakur Mythili Koneru Xuelin Huang Kiran Naqvi William Wierda Prithviraj Bose Elias Jabbour Zeev Estrov Jan Burger Yesid Alvarado April Deshmukh Ami Patel Antonio Cavazos Lina Han Jorge E. Cortes Hagop Kantarjian Michael Andreeff Marina Konopleva |
| author_sort | Prajwal Boddu |
| collection | DOAJ |
| description | Background: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model.Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18–70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/μL was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion.Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19–70). Median number of prior therapies was 1 (1–3). Six and five patients were treated at dose-levels “0” (10 mg) and “1” (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels “0” and “1,” respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ≥ 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy.Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level. |
| first_indexed | 2024-12-10T18:40:19Z |
| format | Article |
| id | doaj.art-c2ad7be1c5364b8ebd00f91dd7c3247a |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T18:40:19Z |
| publishDate | 2018-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c2ad7be1c5364b8ebd00f91dd7c3247a2022-12-22T01:37:41ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-09-01810.3389/fonc.2018.00369414518Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid LeukemiaPrajwal Boddu0Gautam Borthakur1Mythili Koneru2Xuelin Huang3Kiran Naqvi4William Wierda5Prithviraj Bose6Elias Jabbour7Zeev Estrov8Jan Burger9Yesid Alvarado10April Deshmukh11Ami Patel12Antonio Cavazos13Lina Han14Jorge E. Cortes15Hagop Kantarjian16Michael Andreeff17Marina Konopleva18Department of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesEli Lilly and Company, Indianapolis, IN, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Leukemia, University of Texas at MD Anderson Cancer Center, Houston, TX, United StatesBackground: The CXCR4/SDF-1α axis plays a vital role in the retention of stem cells within the bone marrow and downstream activation of cell survival signaling pathways. LY2510924, a second generation CXCR4, showed significant anti-leukemia activity in a murine AML model.Methods: We conducted a phase I study to determine the safety and toxicity of LY2510924, idarubicin and cytarabine (IA) combination therapy in relapsed/refractory (R/R) AML. Eligible patients were 18–70 years of age receiving up to salvage 3 therapy. A peripheral blood absolute blast count of < 20,000/μL was required for inclusion. LY2510924 was administered daily for 7 days followed by IA from day 8. Two dose escalation levels (10 and 20 mg) were evaluated, with a plan to enroll up to 12 patients in the phase I portion.Results: The median age of the enrolled patients (n = 11) was 55 years (range, 19–70). Median number of prior therapies was 1 (1–3). Six and five patients were treated at dose-levels “0” (10 mg) and “1” (20 mg), respectively. Only one patient experiencing a dose limiting toxicity (grade 3 rash and myelosuppression). Three and one complete responses were observed at dose-levels “0” and “1,” respectively; the overall response rate (ORR) was 36% (4 of 11 patients). A ≥ 50% decrease in CXCR4 mean fluorescence intensity was observed in 4 of 9 patients by flow cytometry, indicating incomplete suppression of CXCR4-receptor occupancy.Conclusions: The combination of LY2510924 with IA is safe in R/R AML. Dose-escalation to a 30 mg LY2510924 dose is planned to achieve complete blockade of CXCR4 receptor occupancy, followed by expansion phase at the recommended phase 2 dose-level.https://www.frontiersin.org/article/10.3389/fonc.2018.00369/fullLY2510924idarubicincytarabinerelapsed refractoryacute myeloid leukemiaCXC4 |
| spellingShingle | Prajwal Boddu Gautam Borthakur Mythili Koneru Xuelin Huang Kiran Naqvi William Wierda Prithviraj Bose Elias Jabbour Zeev Estrov Jan Burger Yesid Alvarado April Deshmukh Ami Patel Antonio Cavazos Lina Han Jorge E. Cortes Hagop Kantarjian Michael Andreeff Marina Konopleva Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia Frontiers in Oncology LY2510924 idarubicin cytarabine relapsed refractory acute myeloid leukemia CXC4 |
| title | Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia |
| title_full | Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia |
| title_fullStr | Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia |
| title_full_unstemmed | Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia |
| title_short | Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia |
| title_sort | initial report of a phase i study of ly2510924 idarubicin and cytarabine in relapsed refractory acute myeloid leukemia |
| topic | LY2510924 idarubicin cytarabine relapsed refractory acute myeloid leukemia CXC4 |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00369/full |
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