title: Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia.
abstract: Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Talha
authors.initials: T
authors.lastname: Badar
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, California.
authors.forename: Damian R
authors.initials: DR
authors.lastname: Handisides
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Benito
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Richie
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Karine
authors.initials: K
authors.lastname: Harutyunyan
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, California.
authors.forename: Stew
authors.initials: S
authors.lastname: Kroll
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Threshold Pharmaceuticals, South San Francisco, California.
authors.forename: Tillman
authors.initials: T
authors.lastname: Pearce
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004941:Esophagitis / Q000139:chemically induced; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D000860:Hypoxia; D007938:Leukemia / Q000150:complications / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D010752:Phosphoramide Mustards / Q000008:administration & dosage* / Q000009:adverse effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage; D016879:Salvage Therapy; D013280:Stomatitis / Q000139:chemically induced; D055815:Young Adult
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302