Phase 1 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2015 by Celgene Corporation
Sponsor:
Collaborator:
Agios Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT01915498
First received: July 31, 2013
Last updated: July 1, 2015
Last verified: July 2015
  Purpose

Study AG221-C-001 is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered AG-221 in subjects with advanced hematologic malignancies that harbor an IDH2 mutation. The study includes a dose escalation phase to determine the maximum tolerated dose (MTD) and/or the recommended Pase 2 dose (RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical activity of AG-221 in select populations.


Condition Intervention Phase
Hematologic Neoplasms
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 and Expansion, 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 Celgene Corporation:

Primary Outcome Measures:
  • Adverse Events (AEs) [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: Yes ]
    Number and incidence of Adverse Events for subjects participantscontinuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies.

  • Maximum Tolerated Dose [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: Yes ]
    To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of AG-221 in subjects with advanced hematologic malignancies.

  • Clinical Activity of AG-221 for subjects with relapse ot refractory acute myelogenous leukemia (AML) with Isocitrate dehydrogenase protein 2 (IDH2) mutation [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    For Part 2 of the expansion, response to treatment assessed by the site Investigator and independent central review.


Secondary Outcome Measures:
  • Dose Limiting Toxicities [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: Yes ]
    To describe the dose limiting toxicities (DLTs) of AG-221 in subjects with advanced hematologic malignancies.

  • Pharmacokinetic Cmax [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    Maximum observed concentration in plasma for each dose group and, where appropriate, for the entire population

  • Pharmacokinetic Tmax [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    Time to maximum concentration for each dose group and, where appropriate, for the entire population

  • Clinical Activity pf AG-221 in subjects with hematologic malignancies [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    For all participating subjects, response to treatment assessed by the site Investigator's using International Working Group (IWG) or other appropriate response criteria

  • Pharmacokinetic AUC [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    Area under the plasma concentration‐time curve for each dose group and, where appropriate, for the entire population

  • Pharmacokinetic Elimination half-life [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    Elimination half-life for each dose group and, where appropriate, for the entire population

  • Pharmacodynamics Analyses Plasma [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    To explore the potential relationship of plasma level of AG221 and plasma

  • Pharmacodynamics Analyses Urine [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    To explore the potential relationship of plasma level of AG221 and urine

  • Pharmacodynamics Analyses Bone Marrow (2-HG) [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    To explore the potential relationship of plasma level of AG221 and bone marrow (2-HG)


Estimated Enrollment: 261
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
AG-221 administered orally. Multiple doses.
Drug: AG-221
AG-221 administered orally 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 advanced hematologic malignancy based on local evaluation.
  • Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
  • Subjects must be able and willing to sign an informed consent.
  • Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status (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 (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement, and serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic organ involvement.
  • 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) estimation
  • 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 two highly effective forms of contraception during the study and for 90 days (females and males) following the last dose of AG-221.

Exclusion Criteria:

  • 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 a stable dose of oral steroids post GVHD and/or topical steroids for ongoing skin GVHD is permitted with 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 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 taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2).
  • Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
  • Subjects for whom potentially curative anticancer therapy is available.Subjects who are pregnant or lactating.
  • Subjects with an active severe infection that required anti-infective therapy 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 known hypersensitivity to any of the components of AG-221.
  • Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (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 uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) at screening 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 msec 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) at screening.
  • Subjects taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
  • Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
  • Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.
  • 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.
  • 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: NCT01915498

Contacts
Contact: Eyal Attar, MD 617-649-8675 eyal.attar@agios.com

  Show 25 Study Locations
Sponsors and Collaborators
Celgene Corporation
Agios Pharmaceuticals, Inc.
Investigators
Study Director: Eyal Attar, MD Agios Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT01915498     History of Changes
Other Study ID Numbers: AG-221-C-001
Study First Received: July 31, 2013
Last Updated: July 1, 2015
Health Authority: United States: Food and Drug Administration
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Celgene Corporation:
Acute myeloid leukemia
AML
Myelodysplastic syndrome
MDS
Hematologic malignancies
IDH2
Phase I
AG-221

Additional relevant MeSH terms:
Hematologic Neoplasms
Hematologic Diseases
Neoplasms
Neoplasms by Site

ClinicalTrials.gov processed this record on July 30, 2015