Phase 1/2 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 December 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: December 22, 2015
Last verified: December 2015
  Purpose
Study AG221-C-001 is a Phase 1/2, 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 Phase 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
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1/2, 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 ]
    To assess the safety and tolerability of treatment with AG-221 administered continuously 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) or maximum administered dose (MAD) 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 relapsed or refractory acute myelogenous leukemia (AML) with Isocitrate dehydrogenase protein 2 (IDH2) mutation [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    To assess the efficacy of AG-221 as treatment for subjects with relapsed or refractory AML with an IDH2 mutation


Secondary Outcome Measures:
  • Dose Limiting Toxicities [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: Yes ]
    For the Phase 1 Dose Escalation/Part 1 Expansion, 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 and in the relapse/refractory AML 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 and in the relapse/refractory AML 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 in the Phase 1 Dose Escalation/Part 1 Expansion, 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 and in the relapse/refractory AML 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 and in the relapse/refractory AML 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 2-HG levels, where appropriate for the entire population and in the R/R AML population and in the relapse/refractory AML population

  • Pharmacodynamics Analyses Urine [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    For the Phase 1 Dose Escalation/Part 1 Expansion, to explore the potential relationship of plasma level of AG221 and urine 2-HG for the entire population and in the relapse/refractory AML population

  • 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) for the entire population and in the relapse/refractory AML population

  • Clinical Activity of AG-221 in subjects with Relapse/Refractory AML with an IDH2 mutation [ Time Frame: up to 26 weeks ] [ Designated as safety issue: No ]
    For Expansion phase 2, an independent central review will assess clinical activity


Estimated Enrollment: 375
Study Start Date: August 2013
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (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:

  1. Subject must be greater than or equal to 18 years of age.
  2. Subjects must have an advanced hematologic malignancy including:

Phase 1/ Dose escalation:

  1. Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization (WHO) criteria;

    • Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow).
    • Untreated AML, greater than or equal to 60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor;
  2. Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor.

    Phase 1/Part 1 Expansion:

    Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a Bone marrow transplant (BMT).

    Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT.

    Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy.

    Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3.

    Phase 2:

    Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by:

    • Subjects who relapse after allogeneic transplantation;
    • Subjects in second or later relapse;
    • Subjects who are refractory to second-line induction or re-induction treatment.
  3. Subjects must have documented IDH2 gene-mutated disease:

    • For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.)
    • For subjects in The Phase 2 portion of the trial, central testing of IDH2 mutation is required during screening to confirm eligibility.
  4. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling and urine sampling during the study.

    • The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a "dry tap"), the diagnosis may be made from the core biopsy.
    • Screening bone marrow aspirate and peripheral blood samples are required of all subjects. A bone marrow biopsy must be collected if adequate aspirate is not attainable unless:

      • A bone marrow aspirate and biopsy was performed as part of the standard of care within 28 days prior to the start of the study treatment; and
      • Slides of bone marrow aspirate, biopsy and stained peripheral blood smear are available for both local and central pathology reviewers; and
      • A bone marrow aspirate sample acquired within 28 days prior to the start of study treatment has been sent for cytogenetic analysis.
  5. Subjects must be able to understand and willing to sign an informed consent. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or sites Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
  6. Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.
  7. 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.
  8. Subjects must have adequate hepatic function as evidenced by:

    • Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ involvement, following approval by the Medical Monitor;
    • Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) ≤3.0 × ULN (Upper limit of normal), unless considered due to leukemic organ involvement.
  9. Subjects must have adequate renal function as evidenced by:

    • Serum creatinine ≤2.0 × ULN OR

    • Creatinine clearance greater than 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine

  10. Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer. (Subjects with residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.)
  11. Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.
  12. 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 sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 90 days (females and males) following the last dose of AG-221. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization.
  13. Able to adhere to the study visit schedule (ie, clinic visits at the study sites are mandatory, unless noted otherwise for particular study visits) and other protocol requirements.

Exclusion Criteria:

  1. 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.)
  2. 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).
  3. 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.
  4. 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).
  5. 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.
  6. Subjects for whom potentially curative anticancer therapy is available.
  7. Subjects who are pregnant or lactating.
  8. 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).
  9. Subjects with known hypersensitivity to any of the components of AG-221.
  10. 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.
  11. Subjects with a history of myocardial infarction within the last 6 months of screening.
  12. 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.
  13. Subjects with known unstable or uncontrolled angina pectoris.
  14. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
  15. 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.
  16. 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.
  17. Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
  18. 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.
  19. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
  20. Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.
  21. Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
  22. In the Phase 2 portion of the trial only, subjects who have previously received treatment with an inhibitor of Isocitrate dehydrogenase protein (IDH).
  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: Jay Mei, MD 1 (908) 673 2091
Contact: Eyal Attar, MD (617) 649 8675 eyal.attar@agios.com

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010-301
Stanford Cancer Center Recruiting
Stanford, California, United States, 94305
United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
United States, Florida
University of Miami Sylvester Cancer Center Recruiting
Miami, Florida, United States, 33136
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611-3008
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02117
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University Recruiting
St. Louis, Missouri, United States, 63110
United States, New York
Cornell University Weill Medical College Recruiting
New York, New York, United States, 10065
Memorial Sloan-Kettering Cancer Center - NYC Recruiting
New York, New York, United States, 10065
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Ohio State University Recruiting
Gahanna, Ohio, United States, 43230
United States, Oregon
Oregon Health and Science University (OHSU) Not yet recruiting
Portland, Oregon, United States, 97201-3098
United States, Tennessee
Sarah Cannon Research Institute Drug Development Unit Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
UT Southwestern Medical Center at Dallas Recruiting
Dallas, Texas, United States, 75390-85520
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
France
Institut Bergonié Départment Oncologie Recruiting
Bordeaux, France, 33076
Hospital Saint Louis Not yet recruiting
Paris, France, 75010
Hospital haut leveque Recruiting
Pessac, France, 33604
CHU Purpan Recruiting
Toulouse, France, 31059
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Sponsors and Collaborators
Celgene Corporation
Agios Pharmaceuticals, Inc.
Investigators
Study Director: Jay Mei, MD Celgene Corporation
  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: December 22, 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
Phase II
AG-221
relapse AML
refractory AML

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

ClinicalTrials.gov processed this record on February 04, 2016