Clinical Trial - NCT02074839

Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation

Recruiting

Sponsor: Agios Pharmaceuticals, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT02074839

Protocol Info

Short Description: Phase 1 AG-120 For Advanced Hem Malig With IDH1 Mutation
Long Description: A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects with Advanced Hematologic Malignancies with an IDH1 Mutation
MGH Status: Open
Sponsor: Agios Pharmaceuticals
Disease Program: Leukemia

Next Steps


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Purpose

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Additionally, the study includes a substudy evaluating the safety and tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome with an IDH1 mutation. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.
Condition Title Intervention Phase
Relapsed or Refractory Acute Myeloid Leukemia (AML) Untreated AML Other IDH1-mutated Positive Hematologic Malignancies Myelodysplastic Syndromes AG-120 Phase 1
Study Type Interventional
Official Title A Phase I, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation

Primary Outcome Measures

Safety/tolerability: incidence of adverse events. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Assess clinical activity of AG-120 in subjects with relapsed or refractory AML who are enrolled in the Expansion Phase. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Safety/tolerability of treatment with AG-120 in subjects with relapsed or refractory myelodysplastic syndrome. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Assess clinical activity of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]


Secondary Outcome Measures

Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Pharmacodynamic relationship of AG-120 and 2-HG. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Clinical Activity of AG-120 in advanced hematologic malignancies according to the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS or MDS/myeloproliferative neoplasms (MPN). [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Cmax) of AG-120 in subjects with R/R MDS. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Tmax) of AG-120 in subjects with R/R MDS. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (AUC) of AG-120 in subjects with R/R MDS. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Blood and bone marrow sampling at specified time points for determination of 2-HG levels to characterize the percent of 2-HG inhibition of AG-120 in plasma and bone marrow. [Time Frame: up to 26 weeks, on average] [Designated as safety issue: ]

Estimated Enrollment: 291
Study Start Date: March 2014
Estimated Study Completion Date: June 2021
Estimated Primary Completion Date: December 2020
Arms Assigned Interventions

Experimental:AG-120

AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.
Drug:AG-120
AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression, development of other unacceptable toxicity or hematopoietic stem cell transplant.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Key Inclusion Criteria:

  • Subject must be =18 years of age.
  • Subjects must have documented IDH1 R132 gene-mutated advanced hematologic malignancy based on local or central evaluation.
  • Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
  • Subjects must have ECOG PS of 0 to 2.
  • Platelet count =20,000/µL (Transfusions to achieve this level are allowed).
  • Subjects must have adequate hepatic function as evidenced by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =3.0 × ULN, unless considered due to leukemic disease and serum total bilirubin =1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic disease
  • Subjects must have adequate renal function as evidenced by a serum creatinine =2.0 × ULN or creatinine clearance >40mL/min based on Cockroft-Gault glomerular filtration rate (GFR)
  • Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
  • Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy and on the first day of study drug administration.

Key Exclusion Criteria:

  • Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-120, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post HSCT and/or topical for ongoing skin GVHD is permitted.)
  • Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed prior to enrollment and after the start of AG-120).
  • Subjects who received an investigational agent <14 days prior to their first day of study drug administration.
  • Subjects who are pregnant or breastfeeding.
  • Subjects with an active severe infection or with an unexplained fever >38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
  • Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.
  • Subjects with a history of myocardial infarction within the last 6 months of screening.
  • Subjects with a known unstable or uncontrolled angina pectoris.
  • Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
  • Subjects with known unstable or uncontrolled angina pectoris.
  • Subjects with heart-rate corrected QT (QTc) interval =450 ms or other factors that increase the risk of QT prolongation or arrhythmic events.
  • Patients taking medications that are known to prolong the QT interval
  • Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
  • Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
  • Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02074839

Locations

  • United States, Alabama
    • Birmingham, Alabama, United States, 35294
  • United States, Arizona
    • Phoenix, Arizona, United States, 85259
  • United States, California
    • Duarte, California, United States, 91010
    • Los Angeles, California, United States, 90095
    • San Francisco, California, United States, 94143
  • United States, Colorado
    • Aurora, Colorado, United States, 80045
  • United States, Florida
    • Jacksonville, Florida, United States, 32224
    • Miami, Florida, United States, 33136
  • United States, Georgia
    • Atlanta, Georgia, United States, 30322
  • United States, Illinois
    • Chicago, Illinois, United States, 60611
  • United States, Maryland
    • Baltimore, Maryland, United States, 21287
  • United States, Massachusetts
    • Boston, Massachusetts, United States, 02215
  • United States, Missouri
    • Saint Louis, Missouri, United States, 63110
  • United States, New York
    • New York, New York, United States, 10021
    • New York, New York, United States, 10065
  • United States, Ohio
    • Cleveland, Ohio, United States, 44124
    • Columbus, Ohio, United States, 43210
  • United States, Oregon
    • Portland, Oregon, United States, 97239
  • United States, South Carolina
    • Charleston, South Carolina, United States, 29425
  • United States, Tennessee
    • Nashville, Tennessee, United States, 37203
  • United States, Texas
    • Dallas, Texas, United States, 75390
    • Houston, Texas, United States, 77030
  • France,
    • Pessac, , France, 33600
    • Villejuif, , France, 94800

Sponsors and Collaborators

Agios Pharmaceuticals, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT02074839
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Agios Pharmaceuticals, Inc.:

acute myeloid leukemia

AML

myelodysplastic syndrome

MDS

hematologic malignancies

IDH

Untreated AML

IDH1

relapsed AML

refractory AML

Additional relevant MeSH terms:

Leukemia, Myeloid, Acute

Neoplasms

Preleukemia

Hematologic Neoplasms

Myelodysplastic Syndromes

Ivosidenib

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on October 14, 2020