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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Agios Pharmaceuticals, Inc.
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02074839
First received: February 21, 2014
Last updated: August 4, 2014
Last verified: August 2014
  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 three cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.


Condition Intervention Phase
Relapsed/Primary Refractory Acute Myeloid Leukemia (AML)
Recurrent or Refractory Myelodysplastic Syndrome
Drug: AG-120
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, 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

Resource links provided by NLM:


Further study details as provided by Agios Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Safety/tolerability: incidence of adverse events [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
  • 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: Yes ]

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: Yes ]
  • Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
    Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include (but are not limited to) maximum concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.

  • Pharmacodynamic relationship of AG-120 and 2-HG [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
    The potential relationship between plasma exposure of AG-120 and plasma, urine, or bone marrow 2-HG levels will be explored with descriptive and graphical methods.

  • Clinical Activity 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: Yes ]

Estimated Enrollment: 51
Study Start Date: March 2014
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AG-120
AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression or development of other unacceptable toxicity.
Drug: AG-120
AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression or development of other unacceptable toxicity.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Subject must be ≥18 years of age.
  • Subjects must have an advanced hematologic malignancy including: Relapsed and/or primary refractory AML as defined by WHO criteria; OR Untreated AML, ≥60 years of age and not candidates for standard therapy due to age, performance status, and/or adverse risk factors; OR Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the IPSS-R (Greenberg, et al. 2012), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition.
  • Subjects must have documented IDH1 gene-mutated disease based on local 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. Subjects with reproductive potential are defined as one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-120.

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 topical steroids for ongoing skin GVHD is permitted.) Subjects who have achieve a complete remission (CR) or CR with incomplete platelet recovery (CRp) on this study, have been removed to undergo HSCT, and who relapse, may be eligible based on Medical Monitor approval.
  • 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 for up to 28 days after the start of AG-120 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL. Hydroxyurea may be allowed >28 days after the start of AG-120 at the discretion of hte Investigator and approval of the Medical Monitor).
  • Subjects who received an investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
  • 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.
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Contacts
Contact: Molly Prahl, RN 617.649.8635 molly.prahl@agios.com
Contact: Sam Agresta, MD, MPH & TM 617.649.8621 sam.agresta@agios.com

Locations
United States, California
Not yet recruiting
Stanford, California, United States, 94305
United States, Colorado
Recruiting
Aurora, Colorado, United States, 80045
United States, Florida
Not yet recruiting
Miami, Florida, United States, 33136
United States, Illinois
Recruiting
Chicago, Illinois, United States, 60611
United States, Massachusetts
Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Recruiting
New York, New York, United States, 10065
United States, Tennessee
Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Not yet recruiting
Dallas, Texas, United States, 75390
France
Recruiting
Villejuif, France, 94800
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
Investigators
Study Director: Clinical Development Agios Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02074839     History of Changes
Other Study ID Numbers: AG120-C-001
Study First Received: February 21, 2014
Last Updated: August 4, 2014
Health Authority: United States: Food and Drug Administration
France: Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM)

Keywords provided by Agios Pharmaceuticals, Inc.:
acute myeloid leukemia
AML
myelodysplastic syndrome
MDS
hematologic malignancies
IDH
Untreated AML, ≥60 Years of Age and Not a Candidate for Standard Therapy

Additional relevant MeSH terms:
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia
Syndrome
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Disease
Pathologic Processes

ClinicalTrials.gov processed this record on September 16, 2014