title: Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.
abstract: BACKGROUND
  Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.
  
  
  METHODS
  In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312.
  
  
  RESULTS
  Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose).
  
  
  CONCLUSIONS
  Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies.
  
  
  BACKGROUND
  Astex Pharmaceuticals, Stand Up To Cancer.
authors: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA; Cancer Epigenetics Program, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA. Electronic address: jpissa@temple.edu.
authors: Jean-Pierre J
authors: JJ
authors: Issa
authors: Weill Cornell Medical College and New York Presbyterian Hospital, Division of Hematology and Oncology, New York, NY, USA.
authors: Gail
authors: G
authors: Roboz
authors: Duke University Medical Center, Durham, NC, USA.
authors: David
authors: D
authors: Rizzieri
authors: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
authors: Elias
authors: E
authors: Jabbour
authors: University of Chicago, Chicago, IL, USA.
authors: Wendy
authors: W
authors: Stock
authors: Jane Anne Nohl Division of Hematology Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Casey
authors: C
authors: O'Connell
authors: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors: Karen
authors: K
authors: Yee
authors: Mayo Clinic Arizona, Division of Hematology and Medical Oncology, Scottsdale, AZ, USA.
authors: Raoul
authors: R
authors: Tibes
authors: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Elizabeth A
authors: EA
authors: Griffiths
authors: Ohio State University, James Cancer Hospital, Wexner Medical Center, Columbus, OH, USA.
authors: Katherine
authors: K
authors: Walsh
authors: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
authors: Naval
authors: N
authors: Daver
authors: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
authors: Woonbok
authors: W
authors: Chung
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: Sue
authors: S
authors: Naim
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: Pietro
authors: P
authors: Taverna
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: Aram
authors: A
authors: Oganesian
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: Yong
authors: Y
authors: Hao
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: James N
authors: JN
authors: Lowder
authors: Astex Pharmaceuticals, Pleasanton, CA, USA.
authors: Mohammad
authors: M
authors: Azab
authors: University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
authors: Hagop
authors: H
authors: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077209:Decitabine; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: C580831:guadecitabine; D000077209:Decitabine; D001374:Azacitidine