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.

• Authors: 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
• Journal: Frontiers in oncology (Front Oncol) Vol. 8 Pg. 369 ( 2018) ISSN: 2234-943X [Print] Switzerland
• PMID: 30319961 (Publication Type: Journal Article)