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

Haematologica. 2015 Jul;100(7):927-34. doi: 10.3324/haematol.2014.118455. Epub 2015 Feb 14.

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.

Trial registration: ClinicalTrials.gov NCT01037556.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • 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

Associated data

  • ClinicalTrials.gov/NCT01037556