title: A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors.
abstract: OBJECTIVE
  Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100.
  
  
  METHODS
  Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m(2) administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect.
  
  
  RESULTS
  Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m(2) resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m(2), the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m(2) or higher, remained on study for 5-8 cycles.
  
  
  CONCLUSIONS
  PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m(2). Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), LLC, San Antonio, TX, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Wendi V
authors.initials: WV
authors.lastname: Rodrigueza
authors.forename: Drew W
authors.initials: DW
authors.lastname: Rasco
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Alex
authors.initials: A
authors.lastname: Amaya
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Moore
authors.forename: Shari K
authors.initials: SK
authors.lastname: Gaylor
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: Mina P
authors.initials: MP
authors.lastname: Sooch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Woolliscroft
authors.forename: Richard A
authors.initials: RA
authors.lastname: Messmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; C000588986:PNT100; D019253:Proto-Oncogene Proteins c-bcl-2; D004247:DNA