Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia |
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| Authors: | Marina Konopleva Peter F. Thall Cecilia Arana Yi Gautam Borthakur Andrew Coveler Carlos Bueso-Ramos Juliana Benito Sergej Konoplev Yongchuan Gu Farhad Ravandi Elias Jabbour Stefan Faderl Deborah Thomas Jorge Cortes Tapan Kadia Steven Kornblau Naval Daver Naveen Pemmaraju Hoang Q. Nguyen Jennie Feliu Hongbo Lu Caimiao Wei William R. Wilson Teresa J. Melink John C. Gutheil Michael Andreeff Elihu H. Estey Hagop Kantarjian |
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| Affiliation: | 1.Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2.Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;3.Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA;4.Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;5.Auckland Cancer Society Research Centre, University of Auckland, NZ, USA;6.Proacta Inc., La Jolla, CA, USA |
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| Abstract: | We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m2. The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m2 or 4 g/m2 had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556. |
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