title: Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study.
abstract: BACKGROUND
  Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies.
  
  
  METHODS
  We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758.
  
  
  RESULTS
  Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily.
  
  
  CONCLUSIONS
  Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis.
  
  
  BACKGROUND
  Pfizer.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Courtney
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pfizer Oncology, Collegeville, PA, USA.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: O'Connell
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Karen R
authors.initials: KR
authors.lastname: McLachlan
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Levin
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Division of Regenerative Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Electronic address: cjamieson@ucsd.edu.
authors.forename: Catriona
authors.initials: C
authors.lastname: Jamieson
mesh_terms: D000284:Administration, Oral; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007558:Italy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
chemical_list: D001562:Benzimidazoles; D010671:Phenylurea Compounds; C000592580:glasdegib