A PHASE II CLINICAL TRIAL OF GUADECITABINE (SGI-110) FOR PATIENTS WITH PREVIOUSLY UNTREATED MYELODYSPLASTIC SYNDROME
Author(s): ,
Guillermo Garcia-Manero
Affiliations:
Leukemia,MD Anderson Cancer Center,Houston,United States
,
Prithviraj Bose
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Yesid Alvarado
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Gautam Borthakur
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Naval Daver
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Farhad Ravandi-Kashani
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Elias Jabbour
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Koichi Takahashi
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Michael Andreeff
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Tapan Kadia
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Courtney DiNardo
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Jorge Cortes
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Steven Kornblau
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Kiran Naqvi
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Christopher Benton
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Maro Ohanian
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Marina Konopleva
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Zeev Estrov
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Guillermo Montalban Bravo
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Sherry Pierce
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Kristy Bodden
Affiliations:
MD Anderson Cancer Center,Houston,United States
Hagop Kantarjian
Affiliations:
MD Anderson Cancer Center,Houston,United States
EHA Learning Center. Garcia-Manero G. Jun 17, 2018; 214574
Dr. Guillermo Garcia-Manero
Dr. Guillermo Garcia-Manero

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Abstract
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Abstract: S1555

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:00 - 08:15

Location: Room A4

Background
The hypomethylating agents (HMA) azacitidine and decitabine are the standard of care for most patients with higher risk myelodysplastic syndromes (MDS). Guadecitabine (SGI-110) is a next generation dinucleotide HMA with activity in patients with acute myelogenous leukemia and relapsed/refractory MDS. Here, we present results from a prospective ongoing single arm phase II trial for patients with previously untreated MDS. 

Aims
The aim of this trial is to study the safety and clinical activity of guadecitabine in patients with previously untreated MDS.

Methods
Guadecitabine is administered at a dose of 60 mg/m2 subcutaneous daily x 5 days every 28 days.  Supportive care measures such as transfusions and antibiotic therapy are allowed. Patients with int-2 or high risk MDS by IPSS (or more than 10% marrow blasts) not treated with prior chemotherapy are eligible. Patients could have received up to 1 cycle of prior HMA.  Other inclusion criteria include age older than 17 years, adequate performance and renal and hepatic functions. Patients sign informed consent following institutional guidelines. The primary endpoint is achievement of a complete remission (CR). The study is designed with stopping rules for predetermined CR (stop if CR less than X in cohorts of 10 patients) or excess toxicity (cohorts of 5 patients). CR is defined as blasts less than 5% with complete peripheral blood recovery. Overall response rate is calculated using IWG 06 criteria. Toxicity is graded using CTCAE 4.0. Up to 100 patients are planned to be enrolled.

Results
In summary, 83 patients have been treated in this study. Median follow up is 8.6 months (range 1-38). Median age is 69 years (range 22 to 90) and 43% are older than 70 years. 49 patients (59%) are male. 13 (16%) have a diagnosis consistent with CMML. 66 (80%) patients have int-2 disease, 10 (12%) higher risk disease and 6 (7%) int-1 with more than 10% blasts. 46 (55%) patients had poor risk complex cytogenetics, 21 (25%) were diploid. An 81-gene NGS panel was used in all patients at baseline. Most frequent mutations by rank include: TET2 in 36 (43%) pts, TP53 in 25 (30%), ASXL1 in 22 (26%), RUNX1 in18 (21%), EZH2 in 17 (20%), DNMT3A in 13 (15%), IDH1 and NRAS in 10 (12%), GATA2 in 6 (7%). Median number of cycles administered is 5 (1 to 27). 70 patients (84%) are evaluable for response. CR was documented in 16 (23%), CRp in 3 (4%) and hematological improvement in 26 (37%) for an ORR of 64%. Complete marrow response with incomplete count recovery was considered as an HI.  Median number of cycles to best response is 3 (1-12). Of note, 19 (23%) patients have received less than 3 cycles of therapy. The most common related toxicity has been infection. Only 2 (2%) patients have died during the first six weeks of therapy. Median overall survival is 14 months (1-38+). No association between cytogenetics or poor risk mutations and response was observed.

Conclusion
Guadecitabine (SGI-110) is clinically active and safe in this cohort of patients with higher risk MDS and poor risk features. Stopping rules have not been met and the study continues to accrue. Randomized trials will be required to compare guadecitabine with azacitidine or decitabine in the front line setting. 

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Clinical Trial, Hypomethylation, MDS

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