Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

Tracking Information
First Submitted Date ICMJE	July 31, 2013
First Posted Date ICMJE	August 5, 2013
Last Update Posted Date	June 13, 2018
Actual Study Start Date ICMJE	August 27, 2013
Estimated Primary Completion Date	May 31, 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 1, 2015)	Adverse Events (AEs) [ Time Frame: Up to 26 weeks ]To assess the safety and tolerability of treatment with AG-221 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies; Maximum Tolerated Dose [ Time Frame: Up to 26 weeks ]To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or the recommended Phase 2 dose (RP2D) of AG-221 in subjects with advanced hematologic malignancies.; Clinical Activity of AG-221 for subjects with relapsed or refractory acute myelogenous leukemia (AML) with Isocitrate dehydrogenase protein 2 (IDH2) mutation [ Time Frame: Up to 26 weeks ]To assess the efficacy of AG-221 as treatment for subjects with relapsed or refractory AML with an IDH2 mutation
Original Primary Outcome Measures ICMJE; (submitted: August 1, 2013)	Safety/tolerability: incidence of adverse events [ Time Frame: up to 26 weeks, on average ]; Maximum Tolerated Dose/recommended Phase II dose [ Time Frame: up to 26 weeks, on average ]
Change History	Complete list of historical versions of study NCT01915498 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 1, 2015)	Dose Limiting Toxicities [ Time Frame: Up to 26 weeks ]For the Phase 1 Dose Escalation/Part 1 Expansion, to describe the dose limiting toxicities (DLTs) of AG-221 in subjects with advanced hematologic malignancies.; Pharmacokinetic Cmax [ Time Frame: Up to 26 weeks ]Maximum observed concentration in plasma for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population; Pharmacokinetic Tmax [ Time Frame: Up to 26 weeks ]Time to maximum concentration for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population; Clinical Activity pf AG-221 in subjects with hematologic malignancies [ Time Frame: Up to 26 weeks ]For all participating subjects in the Phase 1 Dose Escalation/Part 1 Expansion, response to treatment assessed by the site Investigator's using International Working Group (IWG) or other appropriate response criteria; Pharmacokinetic AUC [ Time Frame: Up to 26 weeks ]Area under the plasma concentration‐time curve for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population; Pharmacokinetic Elimination half-life [ Time Frame: Up to 26 weeks ]Elimination half-life for each dose group and, where appropriate, for the entire population and in the relapse/refractory AML population; Pharmacodynamics Analyses Plasma [ Time Frame: Up to 26 weeks ]To explore the potential relationship of plasma level of AG221 and plasma 2-HG levels, where appropriate for the entire population and in the R/R AML population and in the relapse/refractory AML population; Pharmacodynamics Analyses Urine [ Time Frame: Up to 26 weeks ]For the Phase 1 Dose Escalation/Part 1 Expansion, to explore the potential relationship of plasma level of AG221 and urine 2-HG for the entire population and in the relapse/refractory AML population; Pharmacodynamics Analyses Bone Marrow (2-HG) [ Time Frame: Up to 26 weeks ]To explore the potential relationship of plasma level of AG221 and bone marrow (2-HG) for the entire population and in the relapse/refractory AML population; Clinical Activity of AG-221 in subjects with Relapse/Refractory AML with an IDH2 mutation [ Time Frame: up to 26 weeks ]For Expansion phase 2, an independent central review will assess clinical activity
Original Secondary Outcome Measures ICMJE; (submitted: August 1, 2013)	Dose Limiting Toxicities [ Time Frame: up to 26 weeks, on average ]; Pharmacokinetics [ Time Frame: through Day 29 ]Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include max concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.; Clinical Activity according to the 2006 modified IWG criteria for MDS, MDS/myeloproliferative neoplasms (MPN) or AML [ Time Frame: up to 26 weeks, on average ]; Pharmacodynamics [ Time Frame: up to 26 weeks, on average ]The potential relationship between levels of AG-221 and 2-HG levels will be explored with descriptive and graphical methods.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation
Official Title ICMJE	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
Brief Summary	Study AG221-C-001 is a Phase 1/2, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered AG-221 in subjects with advanced hematologic malignancies that harbor an IDH2 mutation. The study includes a dose escalation phase to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) and an expansion phase to further evaluate the safety, tolerability and clinical activity of AG-221 in select populations.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Hematologic Neoplasms
Intervention ICMJE	Drug: AG-221; AG-221 administered orally on every day of 28 day cycles until disease progression or unacceptable toxicities. Multiple doses.
Study Arms	Experimental: AG-221; AG-221 administered orally. Multiple doses.; Intervention: Drug: AG-221
Publications *	Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S; AG221-C-001 Study Investigators. Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study. JAMA Oncol. 2018 Jan 18. doi: 10.1001/jamaoncol.2017.4695. [Epub ahead of print]; Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, Tallman MS. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731. doi: 10.1182/blood-2017-04-779405. Epub 2017 Jun 6.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: January 30, 2017)	357
Original Estimated Enrollment ICMJE; (submitted: August 1, 2013)	57
Estimated Study Completion Date	May 31, 2019
Estimated Primary Completion Date	May 31, 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Subject must be greater than or equal to 18 years of age.; Subjects must have an advanced hematologic malignancy including: Phase 1/ Dose escalation: 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;; Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor. Phase 1/Part 1 Expansion: Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a Bone marrow transplant (BMT). Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML who have relapsed following a BMT. Arm 3: Untreated AML and age greater than or equal to 60 years that decline standard of care chemotherapy. Arm 4: Isocitrate dehydrogenase protein, 2 (IDH2)-mutated advanced hematologic malignancies not eligible for Arms 1 to 3. Phase 2: Diagnosis of AML according to World Health Organization (WHO) criteria and disease relapsed or refractory as defined by: Subjects who relapse after allogeneic transplantation; Subjects in second or later relapse; Subjects who are refractory to initial induction or re-induction treatment Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17); 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; 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.; 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).; Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.; Platelet count ≥20,000/μL (transfusions to achieve this level are allowed). Subjects with a baseline platelet count of <20,000/μL due to underlying malignancy are eligible with Medical Monitor approval.; Subjects must have adequate hepatic function as evidenced by: Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to Gilbert's disease, a gene mutation in UGT1A1, or leukemic organ involvement, following approval by the Medical Monitor; Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) ≤3.0 × ULN (Upper limit of normal), unless considered due to leukemic organ involvement.; 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; 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.); 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.; 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.; 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: Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-221, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post GVHD and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.); Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for up to 28 days after the start of AG-221 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL as well as prior to enrollment).; Subjects who received a small molecule investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.; Subjects taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2).; Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study unless they can be transferred to other medications within ≥5 half-lives prior to dosing.; Subjects for whom potentially curative anticancer therapy is available.; Subjects who are pregnant or lactating.; Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever >38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).; Subjects with known hypersensitivity to any of the components of AG-221.; Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.; Subjects with a history of myocardial infarction within the last 6 months of screening.; Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) at screening are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.; Subjects with known unstable or uncontrolled angina pectoris.; Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.; Subjects with heart-rate corrected QT (QTc) interval ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening.; Subjects taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing.; Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.; Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.; Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.; Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.; Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.; In the Phase 2 portion of the trial only, subjects who have previously received treatment with an inhibitor of IDH.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	France, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01915498
Other Study ID Numbers ICMJE	AG-221-C-001
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Celgene
Study Sponsor ICMJE	Celgene
Collaborators ICMJE	Agios Pharmaceuticals, Inc.
Investigators ICMJE	Study Director: Mark Frattini, MD Celgene Corporation
PRS Account	Celgene
Verification Date	June 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP