title: In vivo biologic effects of PIXY321, a synthetic hybrid protein of recombinant human granulocyte-macrophage colony-stimulating factor and interleukin-3 in cancer patients with normal hematopoiesis: a phase I study.
abstract: PIXY321 is a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor and interleukin-3 that exhibits biologic effects of both its parent cytokines in vitro and in preclinical studies. To evaluate the clinical safety and hematopoietic effects of this hybrid cytokine, PIXY321 was administered by subcutaneous injection twice daily at doses of 25 to 1,000 micrograms/m2/day over 14 days to 24 patients with sarcoma before chemotherapy as part of a phase I trial. The treatment was associated with significant increases in white blood cell, neutrophil, platelet, and reticulocyte counts (all P < .001). The increase in neutrophil count was dose-related and was seen during treatment with the cytokine, whereas the increase in platelet count was gradual and peaked after the cessation of the cytokine treatment and was not clearly dose related. PIXY321 treatment also increased bone marrow (BM) cellularity and the percentage of BM cells in S phase (P < .001). In addition, there was a significant increase in the number of CD34+ cells and committed and multipotential progenitors in the peripheral blood. The ex vivo expansion capacity of peripheral blood and BM progenitor cells was preserved after the in vivo treatment with PIXY321. The treatment was well tolerated, with the most common side-effect being injection site reactions. The results of this study show the biologic and clinical activity of a genetically engineered fusion molecule of two hematopoietic cytokines in humans with normal hematopoietic function.
authors.affiliation: Department of Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vadhan-Raj
authors.forename: H E
authors.initials: HE
authors.lastname: Broxmeyer
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.forename: J C
authors.initials: JC
authors.lastname: Bandres
authors.forename: E S
authors.initials: ES
authors.lastname: Buescher
authors.forename: R S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: N E
authors.initials: NE
authors.lastname: Papadopoulos
authors.forename: A
authors.initials: A
authors.lastname: Burgess
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: C
authors.initials: C
authors.lastname: Plager
authors.forename: W N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: I
authors.initials: I
authors.lastname: McAlister
authors.forename: L
authors.initials: L
authors.lastname: Garrison
authors.forename: D E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced / Q000517:prevention & control; D000917:Antibody Formation; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004334:Drug Administration Schedule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D007377:Interleukin-3 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects; D011292:Premedication; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D012449:Safety; D012509:Sarcoma / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007377:Interleukin-3; C078524:PIXY321 fusion protein, recombinant; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor