Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.

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/m(2). 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/m(2) or 4 g/m(2) 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.

• 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
• Journal: Haematologica (Haematologica) Vol. 100 Issue 7 Pg. 927-34 (Jul 2015) ISSN: 1592-8721 [Electronic] Italy
• PMID: 25682597 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents, Alkylating
• Biomarkers
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nitrogen Mustard Compounds
• Nitroimidazoles
• PR-104
• Prodrugs
• pimonidazole
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Adult
• Aged
• Anemia (chemically induced, genetics, metabolism, pathology)
• Antigens, Neoplasm (genetics, metabolism)
• Antineoplastic Agents, Alkylating (administration & dosage, adverse effects, metabolism)
• Biomarkers (metabolism)
• Bone Marrow (drug effects, metabolism, pathology)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (genetics, metabolism)
• Enterocolitis (chemically induced, genetics, metabolism, pathology)
• Female
• Gene Expression
• Humans
• Hypoxia (complications, drug therapy, genetics, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Leukemia, Myeloid, Acute (complications, drug therapy, genetics, pathology)
• Male
• Middle Aged
• Neutropenia (chemically induced, genetics, metabolism, pathology)
• Nitrogen Mustard Compounds (administration & dosage, adverse effects, metabolism)
• Nitroimidazoles (pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (complications, drug therapy, genetics, pathology)
• Prodrugs (administration & dosage, adverse effects, metabolism)
• Recurrence
• Remission Induction
• Thrombocytopenia (chemically induced, genetics, metabolism, pathology)