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Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation

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ClinicalTrials.gov Identifier: NCT01915498
Recruitment Status : Active, not recruiting
First Posted : August 5, 2013
Results First Posted : October 23, 2020
Last Update Posted : October 23, 2020
Sponsor:
Collaborator:
Agios Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Celgene

Brief Summary:

The primary objectives of Phase 1 Dose Escalation/Part 1 Expansion are:

  • To assess the safety and tolerability of treatment with enasidenib administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in participants with advanced hematologic malignancies.
  • To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or the recommended Phase 2 dose (RP2D) of enasidenib in participants with advanced hematologic malignancies.

The primary objective of Phase 2 is:

• To assess the efficacy of enasidenib as treatment for participants with relapsed or refractory (R/R) acute myelogenous leukemia (AML) with an IDH2 mutation.


Condition or disease Intervention/treatment Phase
Hematologic Neoplasms Drug: Enasidenib Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 345 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 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
Actual Study Start Date : September 20, 2013
Actual Primary Completion Date : July 25, 2019
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: enasidenib
enasidenib administered orally. Multiple doses will be administered to determine the RP2D.
Drug: Enasidenib
Enasidenib tablets administered orally every day of 28-day treatment cycles until disease progression or unacceptable toxicities.
Other Names:
  • AG-221
  • IDHIFA




Primary Outcome Measures :
  1. Phase 1 Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLT) [ Time Frame: From time of first dose up to the end of Cycle 1; 28 days ]

    Toxicity severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. A DLT was defined as:

    • Non-hematologic toxicities: CTCAE ≥ Grade 3 with the exception of ≥ Grade 3 blood bilirubin increases in participants with a uridine diphosphate- glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) mutation. In participants with a UGT1A1 mutation, blood bilirubin increases of > 5× upper limit of normal (ULN) were considered a DLT.
    • Hematologic toxicities: Prolonged myelosuppression, defined as persistence of ≥ Grade 3 neutropenia or thrombocytopenia (by NCI CTCAE v4.03), leukemia-specific criteria, i.e., marrow cellularity <5% on Day 28 or later from the start of study drug without evidence of leukemia) at least 42 days after the initiation of Cycle 1 therapy. Leukemia-specific grading was used for cytopenias (based on percentage decrease from Baseline: 50 to 75% = Grade 3, >75% = Grade 4)

  2. Phase 1 Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From the first dose of investigational product (IP) up to 28 days after the last dose, up to the data cutoff date of 01 September 2017; median treatment duration in the dose escalation phase was 5.0 months (range 0.4 to 34.2 months). ]

    A TEAE is any adverse event that began or worsened on or after the start of investigational product (IP) through 28 days after the last dose. A treatment-related TEAE is a TEAE that is suspected (possibly or probably related) by the Investigator to be related to the IP. A serious AE is one that at any dose of IP or at any time during the observation period met the following criteria:

    • Resulted in death;
    • Was life threatening;
    • Requires inpatient hospitalization or prolongation of existing hospitalization;
    • Resulted in persistent or significant disability/incapacity;
    • Was a congenital anomaly/birth defect;
    • Was medically important.

    The intensity of each AE was graded from 1 to 5 according to the NCI CTCAE Version 4.03, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).


  3. Phase 1 Dose Expansion: Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From the first dose of investigational product (IP) up to 28 days after the last dose of IP up to the data cutoff date of 01 September 2017; median treatment duration in Part 1 Expansion was 5.2 months (range 0.5 to 32.8 months). ]

    A TEAE is any adverse event that began or worsened on or after the start of investigational product (IP) through 28 days after the last dose. A treatment-related TEAE is a TEAE that is suspected (possibly or probably related) by the Investigator to be related to the IP. A serious AE is one that at any dose of IP or at any time during the observation period met the following criteria:

    • Resulted in death;
    • Was life threatening;
    • Required inpatient hospitalization or prolongation of existing hospitalization;
    • Resulted in persistent or significant disability/incapacity;
    • Was a congenital anomaly/birth defect;
    • Was medically important.

    The intensity of each AE was graded from 1 to 5 according to the NCI CTCAE Version 4.03, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).


  4. Phase 2 Dose Expansion: Investigator Assessed Overall Response Rate (ORR) [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]

    ORR is defined as the percentage of participants achieving an overall response of complete response (CR), CR with incomplete neutrophil recovery (CRi), CR with incomplete platelet recovery (CRp), partial response (PR), or morphologic leukemia-free state (MLFS) based on the 2003 revised International Working Group (IWG) criteria for AML, assessed by the Investigator.

    CR:

    • Absolute neutrophil count (ANC) > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelets < 100 x 10⁹/L)

    PR:

    • Meets hematologic criteria of CR
    • Decrease of BM blasts to 5-25% and decrease of pretreatment BM blast ≥ 50%.

    MLFS:

    • Bone marrow blasts < 5%
    • Absence of blasts with Auer rods
    • Absence of extramedullary disease
    • No hematologic recovery required

  5. Phase 2 Dose Expansion: Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From the first dose of investigational product (IP) up to 28 days after the last dose, up to the data cutoff of date of 01 September 2017; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]

    A TEAE is any adverse event that began or worsened on or after the start of investigational product (IP) through 28 days after the last dose. A treatment-related TEAE is a TEAE that is suspected (possibly or probably related) by the Investigator to be related to the IP. A serious AE is one that at any dose of IP or at any time during the observation period met the following criteria:

    • Resulted in death;
    • Was life threatening;
    • Required inpatient hospitalization or prolongation of existing hospitalization;
    • Resulted in persistent or significant disability/incapacity;
    • Was a congenital anomaly/birth defect;
    • Was medically important.

    The intensity of each AE was graded from 1 to 5 according to the NCI CTCAE Version 4.03, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).


  6. Safety Follow-up: Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From the primary analysis cut-off date of 01 September 2017 to the final analysis cut-off date of 29 July 2019, a maximum of 23 months. ]

    A TEAE is any adverse event that began or worsened on or after the start of investigational product (IP) through 28 days after the last dose. A treatment-related TEAE is a TEAE that is suspected (possibly or probably related) by the Investigator to be related to the IP. A serious AE is one that at any dose of IP or at any time during the observation period met the following criteria:

    • Resulted in death;
    • Was life threatening;
    • Required inpatient hospitalization or prolongation of existing hospitalization;
    • Resulted in persistent or significant disability/incapacity;
    • Was a congenital anomaly/birth defect;
    • Was medically important.

    The intensity of each AE was graded from 1 to 5 according to the NCI CTCAE Version 4.03, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).



Secondary Outcome Measures :
  1. Phase 1 Dose Escalation: Investigator Assessed Overall Response Rate (ORR) by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in the dose escalation phase was 5.0 months (range 0.4 to 34.2 months). ]

    ORR is defined as the percentage of participants achieving an overall response of CR, CRi, CRp, PR, marrow CR (mCR) (for MDS) and MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

    PR:

    • Meets hematologic criteria of CR
    • Decrease of BM blasts to 5-25% and decrease of pretreatment BM blast ≥ 50%.

    MLFS:

    • Bone marrow blasts < 5%
    • Absence of blasts with Auer rods
    • Absence of extramedullary disease
    • No hematologic recovery required

    mCR:

    • Bone marrow myeloblasts ≤ 5% and decreased by ≥ 50%

  2. Phase 1 Dose Expansion: Investigator Assessed Overall Response Rate (ORR) [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]

    ORR is defined as the percentage of participants achieving an overall response of CR, CRi, CRp, PR, mCR (for MDS), or MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

    PR:

    • Meets hematologic criteria of CR
    • Decrease of BM blasts to 5-25% and decrease of pretreatment BM blast ≥ 50%.

    MLFS:

    • Bone marrow blasts < 5%
    • Absence of blasts with Auer rods
    • Absence of extramedullary disease
    • No hematologic recovery required

    mCR:

    • Bone marrow myeloblasts ≤ 5% and decreased by ≥ 50%

  3. Combined Phase 1/2: Investigator Assessed Overall Response Rate in Participants With R/R AML [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure for Phase 1 and 2 R/R AML participants was 5.4 months (range 0.4 to 34.2 months). ]

    For participants with R/R AML ORR is defined as the percentage of participants achieving an overall response of CR, CRi, CRp, PR, or MLFS based on the 2003 revised IWG criteria for AML.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

    PR:

    • Meets hematologic criteria of CR
    • Decrease of BM blasts to 5-25% and decrease of pretreatment BM blast ≥ 50%.

    MLFS:

    • Bone marrow blasts < 5%
    • Absence of blasts with Auer rods
    • Absence of extramedullary disease
    • No hematologic recovery required

  4. Phase 1 Dose Escalation: Complete Response Rate (CRR) by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Escalation was 5.0 months (range 0.4 to 34.2 months). ]

    Complete response rate is defined as the percentage of participants achieving a complete response (CR) based on the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS as assessed by the investigator.

    CR for AML:

    • Absolute neutrophil count (ANC) > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CR for MDS:

    • Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines
    • Peripheral blood:

      • Hemoglobin ≥ 11 g/dL
      • Platelets ≥ 100 × 10⁹/L
      • Neutrophils ≥ 1.0 × 10⁹/L
      • Blasts = 0%

  5. Phase 1 Dose Expansion: Complete Response Rate [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]

    Complete response rate is defined as the percentage of participants achieving a complete response (CR) based on the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS as assessed by the investigator.

    CR for AML:

    • Absolute neutrophil count (ANC) > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CR for MDS:

    • Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines
    • Peripheral blood:

      • Hemoglobin ≥ 11 g/dL
      • Platelets ≥ 100 × 10⁹/L
      • Neutrophils ≥ 1.0 × 10⁹/L
      • Blasts = 0%

  6. Phase 2 Dose Expansion: Complete Response Rate [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]

    Complete response rate is defined as the percentage of participants achieving a complete response (CR) based on the 2003 revised IWG criteria for AML as assessed by the investigator.

    CR for AML:

    • Absolute neutrophil count (ANC) > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

  7. Phase 1 Dose Escalation: Rate of Complete Response and Complete Response With Incomplete Hematological Recovery (CR/CRi/CRp) by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in the Phase 1 Dose Escalation was 5.0 months (range 0.4 to 34.2 months). ]

    The percentage of participants achieving a complete response (CR), CR with incomplete neutrophil recovery (CRi), or a CR with incomplete platelet recovery (CRp), based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS per investigator review.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

  8. Phase 1 Dose Expansion: Rate of Complete Response and Complete Responses With Incomplete Hematological Recovery (CR/CRi/CRp) [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]

    The percentage of participants achieving a complete response (CR), CR with incomplete neutrophil recovery (CRi), or a CR with incomplete platelet recovery (CRp) based on the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS, assessed by the investigator.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

  9. Phase 2 Dose Expansion: Rate of Complete Response and Complete Responses With Incomplete Hematological Recovery (CR/CRi/CRp) [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]

    The percentage of participants achieving a complete response (CR), CR with incomplete neutrophil recovery (CRi), or a CR with incomplete platelet recovery (CRp) based on the 2003 revised IWG criteria for AML, assessed by the Investigator.

    CR:

    • ANC > 1.0 x10⁹/L
    • Platelet count > 100 x10⁹/L
    • Bone marrow (BM) blasts < 5%
    • Absence of blasts with Auer rods
    • Independence of red cell transfusions

    CRi:

    • All CR criteria except for residual neutropenia (ANC < 1.0 x 10⁹/L

    CRp:

    • All CR criteria except for residual thrombocytopenia (platelet counts < 100 x 10⁹/L)

  10. Phase 1 Dose Expansion: Kaplan-Meier Estimate of Duration of Response (DOR) [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; overall median time on follow-up in Phase 1 Dose Expansion was 8.3 months (range 0.5 to 32.8 months). ]

    Among participants who had a response of CR, CRi, CRp, PR, mCR, or MLFS based on the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS, assessed by the Investigator, duration of response was calculated from the date of the first occurrence of response to the date of documented disease relapse, progression, or death due to any cause, whichever occurred first. DOR was estimated using the Kaplan-Meier method.

    Participants without relapse, progressive disease, or death due to any cause were censored at the date of the last adequate response assessment.


  11. Phase 2 Dose Expansion: Kaplan-Meier Estimate of Duration of Response [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; median time on follow-up in Phase 2 was 5.8 months (range 0.4 to 22.5 months). ]

    For participants with an objective response based on the 2003 revised IWG criteria for AML assessed by the Investigator, duration of response was calculated from the date of the first occurrence of response to the date of documented disease relapse, progression, or death due to any cause, whichever occurred first. Participants without relapse, progressive disease or death were censored at the last response assessment date.

    Relapse (for participants who previously attained CR, Cri, CRp or MLFS): BM blasts ≥ 5%, reappearance of blasts in the blood or development of extramedullary disease.

    Disease progression (for participants who previously attained PR): development of new extramedullary disease, or

    For participants with 5% to 67% BM blasts at nadir:

    • a > 50% increase in BM blasts from nadir and that is ≥ 20%.

    For participants with ≥ 67% BM blasts at nadir:

    • a doubling of the nadir absolute peripheral blood (PB) blast count and the final absolute PB blast count > 10 x 10⁹/L.

  12. Phase 1 Dose Expansion: Kaplan-Meier Estimate of Overall Survival [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; overall median time on follow-up in Phase 1 Dose Expansion was 8.3 months (range 0.5 to 32.8 months). ]
    Overall survival is defined as the time from first dose to the date of death due to any cause. Participants still alive were censored at the last date known to be alive or at the data cut-off date, whichever was earlier.

  13. Phase 2 Dose Expansion: Kaplan-Meier Estimate of Overall Survival [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; median time on follow-up in Phase 2 was 5.8 months (range 0.4 to 22.5 months). ]
    Overall survival is defined as the time from first dose to the date of death due to any cause. Participants still alive were censored at the last date known to be alive or at the data cut-off date, whichever was earlier.

  14. Phase 1 Combined: Percentage of Participants Who Achieved 56-Day Red Blood Cell Transfusion Independence Post-baseline [ Time Frame: Baseline to the end of treatment; overall median duration of treatment exposure in Phase 1 combined was 5.1 months (range 0.4, 34.2 months). ]

    Participants who achieved 56-day post-baseline red blood cell (RBC) transfusion independence, i.e. with no RBC transfusions for at least 56 consecutive days during the treatment exposure period, reported by Baseline RBC transfusion dependence status. Participants with at least one transfusion during the Baseline period were considered transfusion dependent at Baseline, where the Baseline period is defined as 28 days before and 28 days after the first dose of treatment for Phase 1.

    Results are reported for all participants in Phase 1 combined and for the subset of participants with R/R AML.


  15. Phase 1 Combined: Percentage of Participants Who Achieved 56-Day Platelet Transfusion Independence Post-baseline [ Time Frame: Baseline to the end of treatment; overall median duration of treatment exposure in Phase 1 combined was 5.1 months (range 0.4, 34.2 months). ]

    Participants who achieved 56-day post-baseline platelet transfusion independence, i.e. with no platelet transfusions for at least 56 consecutive days during the treatment exposure period, reported by Baseline platelet transfusion dependence status. Participants with at least one transfusion during the Baseline period were considered transfusion dependent at Baseline, where the Baseline period is defined as 28 days before and 28 days after the first dose of treatment for Phase 1.

    Results are reported for all participants in Phase 1 combined and for the subset of participants with R/R AML.


  16. Phase 2: Percentage of Participants Who Achieved 56-Day Red Blood Cell Transfusion Independence Post-baseline [ Time Frame: Baseline to the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]
    Participants who achieved 56-day post-baseline red blood cell (RBC) transfusion independence, i.e. with no RBC transfusions for at least 56 consecutive days during the treatment exposure period, reported by Baseline RBC transfusion dependence status. Participants with at least one transfusion during the Baseline period were considered transfusion dependent at Baseline, where the Baseline period is defined as 56 days before the first dose date for Phase 2.

  17. Phase 2: Percentage of Participants Who Achieved 56-Day Platelet Transfusion Independence Post-baseline [ Time Frame: Baseline to the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]
    Participants who achieved 56-day post-baseline platelet transfusion independence, i.e. with no platelet transfusions for at least 56 consecutive days during the treatment exposure period, reported by Baseline platelet transfusion dependence status. Participants with at least one transfusion during the Baseline period were considered transfusion dependent at Baseline, where the Baseline period is defined as 56 days before the first dose date for Phase 2.

  18. Phase 1 Dose Expansion: Kaplan-Meier Estimate of Event Free Survival (EFS) [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; overall median time on follow-up in Phase 1 Dose Expansion was 8.3 months (range 0.5 to 32.8 months). ]
    Event-free survival is defined as the interval from the date of the first dose to the date of documented relapse, progression, or death due to any cause, whichever occurs first. Participants without an EFS event were censored at the date of the last adequate response assessment.

  19. Phase 2 Dose Expansion: Kaplan-Meier Estimate of Event Free Survival [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; median time on follow-up in Phase 2 was 5.8 months (range 0.4 to 22.5 months). ]
    Event-free survival is defined as the interval from the date of the first dose to the date of documented relapse, progression, or death due to any cause, whichever occurred first. Participants without an EFS event were censored at the date of the last adequate response assessment.

  20. Phase 1 Dose Expansion: Kaplan-Meier Estimate of Duration of Complete Response (DOCR) [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; overall median time on follow-up in Phase 1 Dose Expansion was 8.3 months (range 0.5 to 32.8 months). ]

    Among participants who had a response of CR based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS assessed by the Investigator, duration of complete response was calculated from the date of the first occurrence of complete response to the date of documented disease relapse, progression or death, whichever occurred earlier. DOCR was estimated using the Kaplan-Meier method.

    Participants without relapse, progressive disease, or death due to any cause were censored at the date of the last adequate response assessment.


  21. Phase 2 Dose Expansion: Duration of Complete Response [ Time Frame: From first dose of study treatment to the data cut-off date of 01 September 2017; median time on follow-up in Phase 2 was 5.8 months (range 0.4 to 22.5 months). ]

    Among participants who had a response of CR based on the 2003 revised IWG criteria for AML assessed by the Investigator, duration of complete response was calculated from the date of the first occurrence of complete response to the date of documented disease relapse, progression or death, whichever occurred earlier. DOCR was estimated using the Kaplan-Meier method.

    Participants without relapse, progressive disease, or death due to any cause were censored at the date of the last adequate response assessment.


  22. Phase 1 Dose Escalation: Time to First Response by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Escalation was 5.0 months (range 0.4 to 34.2 months). ]
    Time to response is defined as the time from the date of first dose to the date of the first occurrence of response of CR, CRi, CRp, PR, mCR (for MDS) or MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS as assessed by the Investigator.

  23. Phase 1 Dose Expansion: Time to First Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]
    Time to response is defined as the time from the date of first dose to the date of the first occurrence of response of CR, CRi, CRp, PR, mCR (for MDS) or MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS as assessed by the Investigator.

  24. Phase 2 Dose Expansion: Time to First Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]
    Time to response is defined as the time from the date of first dose to the date of the first occurrence of response of CR, CRi, CRp, PR, or MLFS based on the 2003 revised IWG criteria for AML as assessed by the Investigator.

  25. Phase 1 Dose Escalation: Time to Best Response by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 1 Dose Escalation was 5.0 months (range 0.4 to 34.2 months). ]
    Time to best response is defined as the time from the date of the first dose to the date of the first occurrence of best response according to the following hierarchical order: CR, CRi/CRp, PR, mCR (for MDS) / MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS per investigator assessment.

  26. Phase 1 Dose Expansion: Time to Best Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Part 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]
    Time to best response is defined as the time from the date of the first dose to the date of the first occurrence of best response according to the following hierarchical order: CR, CRi/CRp, PR, mCR (for MDS) / MLFS (for AML) based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS per investigator assessment.

  27. Phase 2 Dose Expansion: Time to Best Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]
    Time to best response is defined as the time from the date of the first dose to the date of the first occurrence of best response according to the following hierarchical order: CR, CRi/CRp, PR, or MLFS based on the 2003 revised IWG criteria for AML per investigator assessment.

  28. Phase 1 Dose Escalation: Time to Complete Response by Total Daily Dose [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in the Phase 1 Dose Escalation phase was 5.0 months (range 0.4 to 34.2 months). ]
    Time to complete response is defined as the time from the date of the first dose to the date of the first complete response based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS per investigator assessment.

  29. Phase 1 Dose Expansion: Time to Complete Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Part 1 Dose Expansion was 5.2 months (range 0.5 to 32.8 months). ]
    Time to complete response is defined as the time from the date of the first dose to the date of the first complete response based on the 2003 revised IWG criteria for AML and 2006 modified IWG criteria for MDS per investigator assessment.

  30. Phase 2 Dose Expansion: Time to Complete Response [ Time Frame: Response assessments were performed every 28 days through Month 12 and every 56 days thereafter until the end of treatment; median duration of treatment exposure in Phase 2 was 5.3 months (range 0.4 to 22.5 months). ]
    Time to complete response is defined as the time from the date of the first dose to the date of the first complete response based on the 2003 revised IWG criteria for AML per investigator assessment.

  31. Phase 1: Area Under the Plasma Concentration Time Curve From Time Zero to 8 Hours Postdose (AUC0-8) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Dose Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for assessment of enasidenib pharmacokinetics (PK).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  32. Phase 1: Area Under the Plasma Concentration Time Curve From Time Zero to 10 Hours Postdose (AUC0-10) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule.


  33. Phase 1: Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  34. Phase 1: Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours Postdose (AUC0-72) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 72 hours post-dose (AUC0-72) was calculated using the linear trapezoidal rule.


  35. Phase 1: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  36. Phase 1: Maximum Concentration of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  37. Phase 1: Time to Maximum Concentration (Tmax) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  38. Phase 1: Apparent Terminal Phase Half-life (t½) of Enasidenib After a Single Oral Dose on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    T1/2 was not calculated when the terminal elimination rate constant (λz) was not estimable.


  39. Phase 1: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of Enasidenib After Multiple Oral Doses [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  40. Phase 1: AUC From Time Zero to 10 Hours Postdose (AUC0-10) of Enasidenib After Multiple Oral Doses [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule.


  41. Phase 1: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Enasidenib After Multiple Oral Doses [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  42. Phase 1: Maximum Concentration (Cmax) of Enasidenib After Multiple Oral Doses [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]
    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  43. Phase 1: Time to Maximum Concentration (Tmax) of Enasidenib After Multiple Oral Doses [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]
    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  44. Phase 2: Area Under the Plasma Concentration Time Curve From Time Zero to 8 Hours Postdose (AUC0-8) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, and 8 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of enasidenib was calculated using the linear trapezoidal rule.


  45. Phase 2: Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours Postdose (AUC 0-24) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  46. Phase 2: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  47. Phase 2: Maximum Concentration (Cmax) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  48. Phase 2: Time to Maximum Concentration (Tmax) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  49. Phase 2: Apparent Terminal Phase Half-life (t1/2) of Enasidenib After Single and Multiple Oral Doses [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  50. Phase 1: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to hour 8 post-dose (AUC 0-8) was calculated using the linear trapezoidal rule.


  51. Phase 1: AUC From Time Zero to 10 Hours Postdose (AUC0-10) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule.


  52. Phase 1: AUC From Time Zero to 24 Hours Postdose (AUC0-24) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  53. Phase 1: AUC From Time Zero to 72 Hours Postdose (AUC0-72) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 72 hours post-dose (AUC0-72) was calculated using the linear trapezoidal rule.


  54. Phase 1: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  55. Phase 1: Maximum Concentration of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  56. Phase 1: Time to Maximum Concentration (Tmax) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  57. Phase 1: Apparent Terminal Phase Half-life (t½) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    t1/2 was not calculated when the terminal elimination rate constant (λz) was not estimable.


  58. Phase 1: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  59. Phase 1: AUC From Time Zero to 10 Hours Postdose (AUC0-10) of AGI-16903 After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 10 hours post-dose (AUC0-10) was calculated using the linear trapezoidal rule.


  60. Phase 1: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of AGI-16903 After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  61. Phase 1: Maximum Concentration (Cmax) of AGI-16903 After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]
    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  62. Phase 1: Time to Maximum Concentration (Tmax) of AGI-16903 After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]
    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  63. Phase 2: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, and 8 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  64. Phase 2: AUC From Time Zero to 24 Hours Postdose (AUC0-24) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  65. Phase 2: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t) was calculated using the linear trapezoidal rule.


  66. Phase 2: Maximum Concentration (Cmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  67. Phase 2: Time to Maximum Concentration (Tmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  68. Phase 2: Apparent Terminal Phase Half-life (t1/2) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose. ]
    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

  69. Phase 1 and 2: AUC From Time Zero to 8 Hours Postdose (AUC0-8) After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, and 8 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  70. Phase 1 and 2: AUC From Time Zero to 24 Hours Postdose (AUC0-24) After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  71. Phase 1 and 2: Maximum Concentration (Cmax) After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  72. Phase 1 and 2: Time to Maximum Concentration (Tmax) After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    Plasma enasidenib was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  73. Phase 1 and 2: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, and 8 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) was calculated using the linear trapezoidal rule.


  74. Phase 1 and 2: AUC From Time Zero to 24 Hours Postdose (AUC0-24) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.

    Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) was calculated using the linear trapezoidal rule.


  75. Phase 1 and 2: Maximum Concentration (Cmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  76. Phase 1 and 2: Time to Maximum Concentration (Tmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD [ Time Frame: Day -3 (Phase 1 only) predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose or Cycle 1 Day 1 (Phase 2) and Cycle 2 Day 1 (Phase 1 & 2) at predose and 2, 4, 6, 8, and 24 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3) for single dose PK analysis, and underwent PK assessments on Cycle 2, Day 1 for multiple dose (steady-state) PK analysis. Participants in Phase 2 underwent PK assessments on Cycle 1, Day 1 for single dose analysis and on Cycle 2, Day 1 for multiple dose (steady-state) analysis.

    AGI-16903 is a primary metabolite of enasidenib. Plasma AGI-16903 was measured using validated liquid chromatography-mass spectrometry methods (LC-MS/MS). The lower limit of quantification (LLOQ) in plasma was 1.00 ng/mL.


  77. Phase 1: Percent Change From Baseline for Area Under the Effect Concentration Time Curve From Time 0 to 10 Hours Postdose (%BAUEC0-10) of 2-hydroxyglutarate (2-HG) on Day -3 [ Time Frame: Screening visit, Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma 2-HG was measured using qualified LC-MS/MS in order to characterize the pharmacodynamic (PD) effects of enasidenib; the LLOQ was 30.0 ng/mL.

    Area under the effect concentration time curve from time point zero (predose) up to 10 hours postdose (AUEC0-10) was calculated using the linear trapezoid rule. Percent change from Baseline for AUEC0-10 was calculated as (AUEC0-10 minus [Baseline*Tlast]) / (Baseline*Tlast) * 100, where Tlast corresponded to 10 hours and Baseline was equal to the average of the Screening and Day -3 (predose) 2-HG values.

    Data reported are the arithmetic mean and relative standard deviation expressed as a percentage.


  78. Phase 1: Minimum Percent Change From Baseline Response Value Post-dose Over 10 Hours (%BRmin) for 2-HG After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Screening visit, Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma 2-HG was measured using qualified LC-MS/MS in order to characterize the pharmacodynamic (PD) effects of enasidenib; the LLOQ was 30.0 ng/mL.

    Minimum percent change from Baseline response value post-dose over 10 hours was calculated as:

    (minimum observed concentration post-dose over 10 hours [Rmin] - Baseline) / Baseline * 100. Baseline was equal to the average of the Screening and Day -3 (predose) 2-HG values.

    Data reported are the arithmetic mean and relative standard deviation expressed as a percentage.


  79. Phase 1: Time of Minimum Observed Concentration Over 72 Hours Postdose (Tmin) of 2-HG After a Single Oral Dose of Enasidenib on Day -3 [ Time Frame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours post-dose. ]

    The first 3 participants enrolled in each cohort of the dose escalation phase and the first 15 participants enrolled in each arm of Phase 1 Expansion received a single dose of enasidenib three days prior to starting the 28-day dosing regimen (Day -3).

    Plasma 2-HG was measured using qualified LC-MS/MS, the LLOQ was 30.0 ng/mL.


  80. Phase 1: Percent Change From Baseline for Area Under the Effect Concentration Time Curve From Time 0 to 10 Hours Postdose of 2-HG After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1, Day 15 and Cycle 2, Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    Plasma 2-HG was measured using qualified LC-MS/MS, the LLOQ was 30.0 ng/mL. Area under the effect concentration time curve from time point zero (predose) up to 10 hours postdose (AUEC0-10) was calculated using the linear trapezoid rule. Percent change from baseline for AUEC0-10 was calculated as:

    (AUEC0-10 minus [Baseline*Tlast]) / (Baseline*Tlast) * 100, where Tlast corresponded to 10 hours and Baseline was equal to the average of the Screening and Day -3 (predose) 2-HG values.

    Data reported are the arithmetic mean and relative standard deviation expressed as a percentage.


  81. Phase 1: Minimum Percent Change From Baseline Response Value Post-dose Over 10 Hours (%BRmin) for 2-HG After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1, Day 15 and Cycle 2, Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]

    Plasma 2-HG was measured using qualified LC-MS/MS, the LLOQ was 30.0 ng/mL.

    Minimum percent change from Baseline response value post-dose over 10 hours was calculated as:

    (minimum observed concentration post-dose over 10 hours [Rmin] - Baseline) / Baseline * 100. Baseline was equal to the average of the Screening and Day -3 (predose) 2-HG values.

    Data reported are the arithmetic mean and relative standard deviation expressed as a percentage.


  82. Phase 1: Time of Minimum Observed Concentration Over 10 Hours Postdose (Tmin) of 2-HG After Multiple Oral Doses of Enasidenib [ Time Frame: Cycle 1, Day 15 and Cycle 2, Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose. ]
    Plasma 2-HG was measured using qualified LC-MS/MS, the LLOQ was 30.0 ng/mL.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 (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 initial induction or re-induction treatment
    • Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk status according to National Comprehensive Cancer Network (NCCN) Guidelines. Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17)
  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 of bone marrow aspirate and peripheral blood, 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, 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 120 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 Cycle 1, Day 1 (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 ( IDH).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01915498


Locations
Show Show 24 study locations
Sponsors and Collaborators
Celgene
Agios Pharmaceuticals, Inc.
Investigators
Layout table for investigator information
Study Director: Mark Frattini, MD Celgene Corporation
  Study Documents (Full-Text)

Documents provided by Celgene:
Statistical Analysis Plan  [PDF] October 4, 2019
Study Protocol  [PDF] October 17, 2017

Publications of Results:
Other Publications:

Layout table for additonal information
Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT01915498    
Other Study ID Numbers: AG-221-C-001
2013-001784-23 ( EudraCT Number )
First Posted: August 5, 2013    Key Record Dates
Results First Posted: October 23, 2020
Last Update Posted: October 23, 2020
Last Verified: October 2020
Keywords provided by Celgene:
acute myeloid leukemia
AML
myelodysplastic syndrome
MDS
hematologic malignancies
IDH2
Phase I
Phase II
AG-221
relapse AML
refractory AML
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases