Phase I Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

This study is currently recruiting participants.
Verified April 2014 by Agios Pharmaceuticals, Inc.
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT01915498
First received: July 31, 2013
Last updated: April 8, 2014
Last verified: April 2014
  Purpose

The purpose of this Phase I, multi-center study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-221 in advanced hematologic malignancies that harbor an IDH2 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-221 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-221 to further evaluate the safety, tolerability, and clinical activity of the MTD. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.


Condition Intervention Phase
Relapsed and/or Primary Refractory AML as Defined by WHO Criteria
Untreated AML, ≥60 Years of Age and Not a Candidate for Standard Therapy
Recurrent or Refractory Myelodysplastic Syndrome
Drug: AG-221
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 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 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/recommended Phase II dose [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Dose Limiting Toxicities [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics [ 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 max concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.

  • Clinical Activity according to the 2006 modified IWG criteria for MDS, MDS/myeloproliferative neoplasms (MPN) or AML [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
  • Pharmacodynamics [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
    The potential relationship between levels of AG-221 and 2-HG levels will be explored with descriptive and graphical methods.


Estimated Enrollment: 57
Study Start Date: August 2013
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AG-221 Drug: AG-221
AG-221 administered orally, twice daily on every day of 28 day cycles until disease progression or unacceptable toxicities. Multiple doses.

  Eligibility

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

Inclusion Criteria:

  • Subject must be ≥18 years of age.
  • Subjects must have documented IDH2 gene-mutated disease based on local evaluation. (Centralized testing will be performed retrospectively.) If not performed prior to screening, gene-mutation analysis should be the first screening procedure performed.
  • Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
  • Subjects or their legal representatives must be able to understand and sign an informed consent.
  • Subjects must have ECOG PS of 0 to 2.
  • Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed.) Subjects with a baseline platelet count of <20,000/µL due to underlying malignancy are eligible with Medical Monitor approval.
  • Subjects must have adequate hepatic function as evidenced by aspartate aminotransferase, ALT, and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement.
  • Subjects must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN.
  • 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-221.

Exclusion Criteria:

  • Subjects who have previously received AG-221.
  • Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-221, 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 received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for up to 28 days after the start of AG-221 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL as well as prior to enrollment).
  • Subjects who received a small molecule investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
  • Subjects who are pregnant or lactating.
  • 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 uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
  • Subjects with known unstable or uncontrolled angina pectoris.
  • Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
  • Subjects with heart-rate corrected QT (QTc) interval ≥450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
  • Patients taking medications that are known to prolong the QT interval (see Section 9.10.2)
  • Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis C.
  • Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
  • 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: NCT01915498

Contacts
Contact: Caroline Almon, MS 650-776-3955 caroline.almon@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
Recruiting
Miami, Florida, United States, 33136
Recruiting
Sarasota, Florida, United States, 34232
United States, Illinois
Recruiting
Chicago, Illinois, United States, 60611
United States, Massachusetts
Recruiting
Boston, Massachusetts, United States, 02114
United States, New York
Recruiting
New York, New York, United States, 10065
United States, Tennessee
Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
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: NCT01915498     History of Changes
Other Study ID Numbers: AG221-C-001
Study First Received: July 31, 2013
Last Updated: April 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Agios Pharmaceuticals, Inc.:
acute myeloid leukemia
AML
myelodysplastic syndrome
MDS
hematologic malignancies
IDH

Additional relevant MeSH terms:
Neoplasms
Myelodysplastic Syndromes
Preleukemia
Hematologic Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms by Site

ClinicalTrials.gov processed this record on April 23, 2014