Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Original languageEnglish (US)
Article number00369
JournalFrontiers in Oncology
Volume8
Issue numberSEP
DOIs
StatePublished - Sep 24 2018
Externally publishedYes

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Idarubicin
Cytarabine
Acute Myeloid Leukemia
CXCR4 Receptors
Salvage Therapy
Exanthema
Cell Survival
Flow Cytometry
Leukemia
Stem Cells
Fluorescence
Bone Marrow
Safety
Therapeutics

Keywords

  • Acute myeloid leukemia
  • Cxc4
  • Cytarabine
  • Idarubicin
  • Relapsed refractory

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. / Boddu, Prajwal; Borthakur, Gautam; Koneru, Mythili; Huang, Xuelin; Naqvi, Kiran; Wierda, William; Bose, Prithviraj; Jabbour, Elias; Estrov, Zeev; Burger, Jan; Alvarado, Yesid; Dekmush, April; Patel, Ami; Cavazos, Antonio; Han, Lina; Cortes, Jorge E.; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina.

In: Frontiers in Oncology, Vol. 8, No. SEP, 00369, 24.09.2018.

Research output: Contribution to journalArticle

Boddu, P, Borthakur, G, Koneru, M, Huang, X, Naqvi, K, Wierda, W, Bose, P, Jabbour, E, Estrov, Z, Burger, J, Alvarado, Y, Dekmush, A, Patel, A, Cavazos, A, Han, L, Cortes, JE, Kantarjian, H, Andreeff, M & Konopleva, M 2018, 'Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia', Frontiers in Oncology, vol. 8, no. SEP, 00369. https://doi.org/10.3389/fonc.2018.00369
Boddu, Prajwal ; Borthakur, Gautam ; Koneru, Mythili ; Huang, Xuelin ; Naqvi, Kiran ; Wierda, William ; Bose, Prithviraj ; Jabbour, Elias ; Estrov, Zeev ; Burger, Jan ; Alvarado, Yesid ; Dekmush, April ; Patel, Ami ; Cavazos, Antonio ; Han, Lina ; Cortes, Jorge E. ; Kantarjian, Hagop ; Andreeff, Michael ; Konopleva, Marina. / Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. In: Frontiers in Oncology. 2018 ; Vol. 8, No. SEP.
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title = "Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia",
abstract = "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.",
keywords = "Acute myeloid leukemia, Cxc4, Cytarabine, Idarubicin, Relapsed refractory",
author = "Prajwal Boddu and Gautam Borthakur and Mythili Koneru and Xuelin Huang and Kiran Naqvi and William Wierda and Prithviraj Bose and Elias Jabbour and Zeev Estrov and Jan Burger and Yesid Alvarado and April Dekmush and Ami Patel and Antonio Cavazos and Lina Han and Cortes, {Jorge E.} and Hagop Kantarjian and Michael Andreeff and Marina Konopleva",
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doi = "10.3389/fonc.2018.00369",
language = "English (US)",
volume = "8",
journal = "Frontiers in Oncology",
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TY - JOUR

T1 - Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

AU - Boddu, Prajwal

AU - Borthakur, Gautam

AU - Koneru, Mythili

AU - Huang, Xuelin

AU - Naqvi, Kiran

AU - Wierda, William

AU - Bose, Prithviraj

AU - Jabbour, Elias

AU - Estrov, Zeev

AU - Burger, Jan

AU - Alvarado, Yesid

AU - Dekmush, April

AU - Patel, Ami

AU - Cavazos, Antonio

AU - Han, Lina

AU - Cortes, Jorge E.

AU - Kantarjian, Hagop

AU - Andreeff, Michael

AU - Konopleva, Marina

PY - 2018/9/24

Y1 - 2018/9/24

N2 - 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.

AB - 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.

KW - Acute myeloid leukemia

KW - Cxc4

KW - Cytarabine

KW - Idarubicin

KW - Relapsed refractory

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U2 - 10.3389/fonc.2018.00369

DO - 10.3389/fonc.2018.00369

M3 - Article

AN - SCOPUS:85055211040

VL - 8

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

IS - SEP

M1 - 00369

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