Clinical trial NCT01915498: Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematologic Neoplasms
Keywords: acute myeloid leukemia
AML
myelodysplastic syndrome
MDS
hematologic malignancies
IDH2
Phase I
Phase II
AG-221
relapse AML
refractory AML
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Agios Pharmaceuticals, Inc.
First posted: 2013-08-05
Enrollment: 345
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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).

Primary outcomes:
measure: Phase 1 Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: From time of first dose up to the end of Cycle 1; 28 days
measure: Phase 1 Dose Escalation: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: 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).
measure: Phase 1 Dose Expansion: Number of Participants With Treatment Emergent Adverse Events
timeFrame: 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).
measure: Phase 2 Dose Expansion: Investigator Assessed Overall Response Rate (ORR)
timeFrame: 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).
measure: Phase 2 Dose Expansion: Number of Participants With Treatment Emergent Adverse Events
timeFrame: 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).
measure: Safety Follow-up: Number of Participants With Treatment Emergent Adverse Events
timeFrame: 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.
Secondary outcomes:
measure: Phase 1 Dose Escalation: Investigator Assessed Overall Response Rate (ORR) by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Investigator Assessed Overall Response Rate (ORR)
timeFrame: 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).
measure: Combined Phase 1/2: Investigator Assessed Overall Response Rate in Participants With R/R AML
timeFrame: 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).
measure: Phase 1 Dose Escalation: Complete Response Rate (CRR) by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Complete Response Rate
timeFrame: 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).
measure: Phase 2 Dose Expansion: Complete Response Rate
timeFrame: 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).
measure: Phase 1 Dose Escalation: Rate of Complete Response and Complete Response With Incomplete Hematological Recovery (CR/CRi/CRp) by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Rate of Complete Response and Complete Responses With Incomplete Hematological Recovery (CR/CRi/CRp)
timeFrame: 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).
measure: Phase 2 Dose Expansion: Rate of Complete Response and Complete Responses With Incomplete Hematological Recovery (CR/CRi/CRp)
timeFrame: 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).
measure: Phase 1 Dose Expansion: Kaplan-Meier Estimate of Duration of Response (DOR)
timeFrame: 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).
measure: Phase 2 Dose Expansion: Kaplan-Meier Estimate of Duration of Response
timeFrame: 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).
measure: Phase 1 Dose Expansion: Kaplan-Meier Estimate of Overall Survival
timeFrame: 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).
measure: Phase 2 Dose Expansion: Kaplan-Meier Estimate of Overall Survival
timeFrame: 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).
measure: Phase 1 Combined: Percentage of Participants Who Achieved 56-Day Red Blood Cell Transfusion Independence Post-baseline
timeFrame: 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).
measure: Phase 1 Combined: Percentage of Participants Who Achieved 56-Day Platelet Transfusion Independence Post-baseline
timeFrame: 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).
measure: Phase 2: Percentage of Participants Who Achieved 56-Day Red Blood Cell Transfusion Independence Post-baseline
timeFrame: 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).
measure: Phase 2: Percentage of Participants Who Achieved 56-Day Platelet Transfusion Independence Post-baseline
timeFrame: 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).
measure: Phase 1 Dose Expansion: Kaplan-Meier Estimate of Event Free Survival (EFS)
timeFrame: 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).
measure: Phase 2 Dose Expansion: Kaplan-Meier Estimate of Event Free Survival
timeFrame: 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).
measure: Phase 1 Dose Expansion: Kaplan-Meier Estimate of Duration of Complete Response (DOCR)
timeFrame: 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).
measure: Phase 2 Dose Expansion: Duration of Complete Response
timeFrame: 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).
measure: Phase 1 Dose Escalation: Time to First Response by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Time to First Response
timeFrame: 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).
measure: Phase 2 Dose Expansion: Time to First Response
timeFrame: 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).
measure: Phase 1 Dose Escalation: Time to Best Response by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Time to Best Response
timeFrame: 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).
measure: Phase 2 Dose Expansion: Time to Best Response
timeFrame: 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).
measure: Phase 1 Dose Escalation: Time to Complete Response by Total Daily Dose
timeFrame: 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).
measure: Phase 1 Dose Expansion: Time to Complete Response
timeFrame: 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).
measure: Phase 2 Dose Expansion: Time to Complete Response
timeFrame: 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).
measure: 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
timeFrame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose.
measure: 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
timeFrame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase 1: Maximum Concentration of Enasidenib After a Single Oral Dose on Day -3
timeFrame: 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.
measure: Phase 1: Time to Maximum Concentration (Tmax) of Enasidenib After a Single Oral Dose on Day -3
timeFrame: 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.
measure: Phase 1: Apparent Terminal Phase Half-life (t½) of Enasidenib After a Single Oral Dose on Day -3
timeFrame: 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.
measure: Phase 1: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of Enasidenib After Multiple Oral Doses
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose.
measure: Phase 1: AUC From Time Zero to 10 Hours Postdose (AUC0-10) of Enasidenib After Multiple Oral Doses
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Enasidenib After Multiple Oral Doses
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: Maximum Concentration (Cmax) of Enasidenib After Multiple Oral Doses
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: Time to Maximum Concentration (Tmax) of Enasidenib After Multiple Oral Doses
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: 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
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, and 8 hours post-dose.
measure: 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
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: 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
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Maximum Concentration (Cmax) of Enasidenib After Single and Multiple Oral Doses
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Time to Maximum Concentration (Tmax) of Enasidenib After Single and Multiple Oral Doses
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Apparent Terminal Phase Half-life (t1/2) of Enasidenib After Single and Multiple Oral Doses
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: 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
timeFrame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose.
measure: 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
timeFrame: Day -3 prior to the single dose of enasidenib and at 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase 1: Maximum Concentration of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3
timeFrame: 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.
measure: Phase 1: Time to Maximum Concentration (Tmax) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3
timeFrame: 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.
measure: Phase 1: Apparent Terminal Phase Half-life (t½) of AGI-16903 After a Single Oral Dose of Enasidenib on Day -3
timeFrame: 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.
measure: Phase 1: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After Multiple Oral Doses of Enasidenib
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose.
measure: Phase 1: AUC From Time Zero to 10 Hours Postdose (AUC0-10) of AGI-16903 After Multiple Oral Doses of Enasidenib
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of AGI-16903 After Multiple Oral Doses of Enasidenib
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: Maximum Concentration (Cmax) of AGI-16903 After Multiple Oral Doses of Enasidenib
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 1: Time to Maximum Concentration (Tmax) of AGI-16903 After Multiple Oral Doses of Enasidenib
timeFrame: Cycle 2 Day 1 at predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 hours post-dose.
measure: Phase 2: AUC From Time Zero to 8 Hours Postdose (AUC0-8) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, and 8 hours post-dose.
measure: Phase 2: AUC From Time Zero to 24 Hours Postdose (AUC0-24) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Maximum Concentration (Cmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Time to Maximum Concentration (Tmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: Phase 2: Apparent Terminal Phase Half-life (t1/2) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at predose and 2, 4, 6, 8, and 24 hours post-dose.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase 1 and 2: Maximum Concentration (Cmax) After Single and Multiple Oral Doses of Enasidenib 100 mg QD
timeFrame: 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.
measure: Phase 1 and 2: Time to Maximum Concentration (Tmax) After Single and Multiple Oral Doses of Enasidenib 100 mg QD
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase 1 and 2: Maximum Concentration (Cmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD
timeFrame: 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.
measure: Phase 1 and 2: Time to Maximum Concentration (Tmax) of AGI-16903 After Single and Multiple Oral Doses of Enasidenib 100 mg QD
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase 1: Minimum Percent Change From Baseline Response Value Post-dose Over 10 Hours (%BRmin) for 2-HG After Multiple Oral Doses of Enasidenib
timeFrame: 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.
measure: Phase 1: Time of Minimum Observed Concentration Over 10 Hours Postdose (Tmin) of 2-HG After Multiple Oral Doses of Enasidenib
timeFrame: 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.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City Of Hope
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Aurora
country: United States
facility: University Of Colorado Cancer Center
state: Colorado
city: Miami
country: United States
facility: University of Miami Sylvester Cancer Center
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Mass General Brigham Cancer Care, Inc
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Cornell University Weill Medical College
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center - NYC
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Gahanna
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University OHSU
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Drug Development Unit
state: Tennessee
city: Dallas
country: United States
facility: Ut Southwestern Medical Center At Dallas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Bordeaux
country: France
facility: Local Institution - 202
city: Paris
country: France
facility: Local Institution - 204
city: Pessac
country: France
facility: Local Institution - 203
city: Toulouse
country: France
facility: Local Institution - 205
city: Villejuif
country: France
facility: Local Institution - 201
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
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