IVOSIDENIB (IVO) IN PATIENTS WITH IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME (R/R MDS): UPDATED ENROLLMENT OF A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY
Author(s): ,
Courtney D DiNardo
Affiliations:
University of Texas MD Anderson Cancer Center,Houston,United States
,
James M Foran
Affiliations:
Mayo Clinic,Jacksonville,United States
,
Justin M Watts
Affiliations:
Sylvester Comprehensive Cancer Center, University of Miami,Miami,United States
,
Eytan M Stein
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Stéphane de Botton
Affiliations:
Institut Gustave Roussy,Villejuif,France
,
Amir T Fathi
Affiliations:
Massachusetts General Hospital Cancer Center,Boston,United States
,
Gabrielle T Prince
Affiliations:
Johns Hopkins Hospital,Baltimore,United States
,
Anthony S Stein
Affiliations:
City of Hope Medical Center,Duarte,United States
,
Richard M Stone
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Prapti A Patel
Affiliations:
University of Texas Southwestern Medical Center,Dallas,United States
,
Gail J Roboz
Affiliations:
The New York Presbyterian Hospital, Weill Cornell Medical College,New York,United States
,
Martha L Arellano
Affiliations:
Winship Cancer Institute, Emory University School of Medicine,Atlanta,United States
,
Harry P Erba
Affiliations:
University of Alabama at Birmingham,Birmingham,United States
,
Arnaud Pigneux
Affiliations:
Centre Hospitalier Universitaire de Bordeaux Haut-Lévêque,Pessac,France
,
Robert K Stuart
Affiliations:
Medical University of South Carolina,Charleston,United States
,
Xavier Thomas
Affiliations:
Centre Hospitalier Universitaire de Lyon-Sud,Lyon,France
,
Geoffrey L Uy
Affiliations:
Washington University School of Medicine,St Louis,United States
,
Hongfang Wang
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Vickie Zhang
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Bin Fan
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Abdulafeez Oluyadi
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Sumita Rai
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Ian R Lemieux
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Hua Liu
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Bin Wu
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Thomas Winkler
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Guillermo Garcia-Manero
Affiliations:
University of Texas MD Anderson Cancer Center,Houston,United States
David A Sallman
Affiliations:
Moffitt Cancer Center,Tampa,United States
(Abstract release date: 05/14/20) EHA Library. D DiNardo C. 06/12/20; 294743; EP826
Courtney D DiNardo
Courtney D DiNardo
Contributions
Abstract

Abstract: EP826

Type: e-Poster

Background
Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with MDS and have been associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) enzyme and is approved in the United States for the treatment of AML with a susceptible IDH1 mutation in adults with newly diagnosed AML ≥75 y of age or having comorbidities precluding the use of intensive induction chemotherapy, and in adults with R/R AML. In the first-in-human, phase 1 dose escalation and expansion study of IVO in patients (pts) with mIDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received 500 mg IVO once daily (QD). The median age was 72.5 y (range 52–78). All pts had received prior treatment for MDS, with 4 (33.3%) and 1 (8.3%) pt having received 2 or ≥3 prior therapies, respectively. Investigator-assessed objective response rate, defined as complete remission (CR), partial remission, and marrow CR, per the International Working Group 2006, was 75.0% (95% CI 42.8%, 94.5%) with a median duration 21.4 mo (95% CI 2.3 mo, not estimable [NE]). Five pts (41.7% [95% CI 15.2%, 72.3%]) had a CR with a median duration of CR NE (95% CI 2.8 mo, NE). Furthermore, 9 (75.0%) pts were transfusion independent for at least 56 days during study treatment. Based on these data, the FDA recently granted a Breakthrough Therapy Designation status for IVO monotherapy in this indication, and the study has been amended to enroll additional mIDH1 R/R MDS pts.

Aims
To assess safety, tolerability, clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD) of treatment with IVO in pts with mIDH1 R/R MDS.

Methods
This is a sub-study of the phase 1 dose escalation and expansion study of IVO in pts with mIDH1 advanced hematologic malignancies (NCT02074839) and will be evaluating IVO in pts with mIDH1 R/R MDS. Pts must have R/R disease after treatment with standard agents indicated for MDS and high disease burden based on transfusion dependence at baseline and/or increased bone marrow blasts (>5%). Pts must have adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN], aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance >40 mL/min). IVO is to be administered at a dose of 500 mg QD orally on Days 1–28 of 28-day cycles. The study is open and will enroll approximately 23 pts from the United States and France.

Results
Results of this currently accruing study are not yet available.

Conclusion
The favorable efficacy and safety of IVO in the small population of pts with mIDH1 R/R MDS in the phase 1 clinical study of pts with mIDH1 hematological malignancies supports further evaluation in this MDS sub-study. This sub-study will provide additional insights into safety, tolerability, clinical activity, and PK/PD of treatment with IVO in pts with mIDH1 R/R MDS.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Ivosidenib, Mutation analysis, Myelodysplasia, Targeted therapy

Abstract: EP826

Type: e-Poster

Background
Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with MDS and have been associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) enzyme and is approved in the United States for the treatment of AML with a susceptible IDH1 mutation in adults with newly diagnosed AML ≥75 y of age or having comorbidities precluding the use of intensive induction chemotherapy, and in adults with R/R AML. In the first-in-human, phase 1 dose escalation and expansion study of IVO in patients (pts) with mIDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received 500 mg IVO once daily (QD). The median age was 72.5 y (range 52–78). All pts had received prior treatment for MDS, with 4 (33.3%) and 1 (8.3%) pt having received 2 or ≥3 prior therapies, respectively. Investigator-assessed objective response rate, defined as complete remission (CR), partial remission, and marrow CR, per the International Working Group 2006, was 75.0% (95% CI 42.8%, 94.5%) with a median duration 21.4 mo (95% CI 2.3 mo, not estimable [NE]). Five pts (41.7% [95% CI 15.2%, 72.3%]) had a CR with a median duration of CR NE (95% CI 2.8 mo, NE). Furthermore, 9 (75.0%) pts were transfusion independent for at least 56 days during study treatment. Based on these data, the FDA recently granted a Breakthrough Therapy Designation status for IVO monotherapy in this indication, and the study has been amended to enroll additional mIDH1 R/R MDS pts.

Aims
To assess safety, tolerability, clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD) of treatment with IVO in pts with mIDH1 R/R MDS.

Methods
This is a sub-study of the phase 1 dose escalation and expansion study of IVO in pts with mIDH1 advanced hematologic malignancies (NCT02074839) and will be evaluating IVO in pts with mIDH1 R/R MDS. Pts must have R/R disease after treatment with standard agents indicated for MDS and high disease burden based on transfusion dependence at baseline and/or increased bone marrow blasts (>5%). Pts must have adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN], aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance >40 mL/min). IVO is to be administered at a dose of 500 mg QD orally on Days 1–28 of 28-day cycles. The study is open and will enroll approximately 23 pts from the United States and France.

Results
Results of this currently accruing study are not yet available.

Conclusion
The favorable efficacy and safety of IVO in the small population of pts with mIDH1 R/R MDS in the phase 1 clinical study of pts with mIDH1 hematological malignancies supports further evaluation in this MDS sub-study. This sub-study will provide additional insights into safety, tolerability, clinical activity, and PK/PD of treatment with IVO in pts with mIDH1 R/R MDS.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Ivosidenib, Mutation analysis, Myelodysplasia, Targeted therapy

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