[ Visit Client Website ]

Before you can access ASH's online program, you must agree to the following:
  • Abstracts submitted to the ASH Annual Meeting are considered embargoed from the time of submission.
  • The media, companies and institutions issuing press releases, and others are required to abide by the embargo policies governing the Society’s annual meeting. Read ASH’s embargo policy for more information.
-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session .

414 Results From the Dose Escalation Phase of a Randomized Phase 1-2 First-in-Human (FIH) Study of SGI-110, a Novel Low Volume Stable Subcutaneous (SQ) Second Generation Hypomethylating Agent (HMA) in Patients with Relapsed/Refractory MDS and AML

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia - Therapy, excluding Transplantation: Chemotherapy for AML
Monday, December 10, 2012: 11:45 AM
B308-B309, Level 3, Building B (Georgia World Congress Center)

Hagop M. Kantarjian, MD1, Gail J. Roboz, MD2, David A. Rizzieri, MD3, Wendy Stock, MD4, Casey L. O'Connell, MD5, Elizabeth A Griffiths, MD6, Karen Yee, MD7*, Raoul Tibes, MD8, Guillermo Garcia-Manero, MD1, Farhad Ravandi, MD1, Katherine Walsh, MD9*, Eric Feldman, MD2, Ellen Ritchie, MD2*, Arati Rao, MD3, Carlos Decastro, MD3*, Aaron D. Schimmer, MD7, Ruben A. Mesa8, Ibrahim Syed, MBBS5*, Gavin Choy, PharmD10, Aram Oganesian, PhD10*, Pietro Taverna, PhD10*, Mohammad Azab, MD10, Woonbok Chung, PhD11* and Jean-Pierre Issa, MD11

1MD Anderson Cancer Center, Houston, TX
2Weill Cornell Medical College, New York, NY
3Duke University Medical Center, Raleigh, NC
4University of Chicago Medical Center, Chicago, IL
5USC Keck School of Medicine, University of Southern California, Los Angeles, CA
6Roswell Park Cancer Institute, Buffalo, NY
7Princess Margaret Hospital, Toronto, Canada
8Mayo Clinic Arizona, Scottsdale, AZ
9Ohio State University, Columbus, OH
10Astex Pharmaceuticals, Inc., Dublin, CA
11Fels Institute, Temple University, Philadelphia, PA

Background:SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs.

Methods:  A randomized Phase 1-2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment.  

Results:  78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29-86), 65% were male, and 82% had ECOG PS of 0-1. Median number of prior regimens was 3 (range 1-9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3-4 hrs). At SGI-110 dose range of 60-125 mg/m2, observed mean decitabine AUCs (88-231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26-64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ~2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed.  Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (~25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ~8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation.  The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose.

Conclusions:  SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ~25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage.

Supported by a grant from Stand Up To Cancer

Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz: Astex Pharmaceuticals: Research Funding. Rizzieri: Astex Pharmaceuticals: Research Funding. Stock: Astex Pharmaceuticals: Research Funding. O'Connell: Astex Pharmaceuticals: Research Funding. Griffiths: Astex Pharmaceuticals: Research Funding. Yee: Astex Pharmaceuticals: Research Funding. Tibes: Astex Pharmaceuticals: Research Funding. Garcia-Manero: Astex Pharmaceuticals: Research Funding. Ravandi: Astex Pharmaceuticals: Research Funding. Walsh: Astex Pharmaceuticals: Research Funding. Feldman: Astex Pharmaceuticals: Research Funding. Ritchie: Astex Pharmaceuticals: Research Funding. Rao: Astex Pharmaceuticals: Research Funding. Decastro: Astex Pharmaceuticals: Research Funding. Schimmer: Astex Pharmaceuticals: Research Funding. Mesa: Astex Pharmaceuticals: Research Funding. Syed: Astex Pharmaceuticals: Research Funding. Choy: Astex Pharmaceuticals: Employment. Oganesian: Astex Pharmaceuticals: Employment. Taverna: Astex Pharmaceuticals: Employment. Azab: Astex Pharmaceuticals: Employment. Chung: Astex Pharmaceuticals: Research Funding. Issa: Astex Pharmaceuticals: Honoraria, Research Funding.

<< Previous Abstract | Next Abstract

*signifies non-member of ASH