- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02632708
Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) With an IDH1 and/or IDH2 Mutation
October 10, 2023 updated by: Institut de Recherches Internationales Servier
A Phase 1, Multicenter, Open-Label, Safety Study of AG-120 or AG-221 in Combination With Induction Therapy and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation
The purpose of this Phase I, multicenter, clinical trial is to evaluate the safety of AG-120 and AG-221 when given in combination with standard AML induction and consolidation therapy.
The study plans to evaluate up to 2 dose levels of AG-120 in participants with an isocitrate dehydrogenase protein 1 (IDH1) mutation and up to 2 dose levels of AG-221 in participants with an isocitrate dehydrogenase protein 2 (IDH2) mutation.
AG-120 or AG-221 will be administered with 2 types of AML induction therapies (cytarabine with either daunorubicin or idarubicin) and 2 types of AML consolidation therapies (mitoxantrone with etoposide [ME] or cytarabine).
After consolidation therapy, participants may continue on to maintenance therapy and receive daily treatment with single-agent AG-120 or AG-221 until relapse, development of an unacceptable toxicity, or hematopoietic stem cell transplant (HSCT).
The study will end when all participants have discontinued study treatment.
Study Overview
Status
Active, not recruiting
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
153
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Ulm, Germany, 89081
- Universitatsklinikum Ulm
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Amsterdam, Netherlands, 1081 HV
- VU Medisch Centrum
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Rotterdam, Netherlands, 3075 EA
- Erasmus MC
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California
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Duarte, California, United States, 91010
- City of Hope
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Los Angeles, California, United States, 90024
- UCLA Medical Center
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Colorado
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Aurora, Colorado, United States, 80045
- University of Colorado
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Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago
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Maryland
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Baltimore, Maryland, United States, 21231
- Johns Hopkins University
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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Boston, Massachusetts, United States, 02114
- Dana Farber Cancer Institute
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New Jersey
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Hackensack, New Jersey, United States, 07601
- Hackensack University Medical Center
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New York
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New York, New York, United States, 10021
- Memorial Sloan Kettering Cancer Center
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Ohio
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Columbus, Ohio, United States, 43210
- Ohio State University
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South Carolina
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Charleston, South Carolina, United States, 29425-0001
- Medical University of South Carolina - PPDS
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Tennessee
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Nashville, Tennessee, United States, 37232
- Vanderbilt University Medical Center
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Texas
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Dallas, Texas, United States, 75390
- University of Texas Southwestern Medical Center
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Houston, Texas, United States, 77030
- MD Anderson Cancer Center
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- Participants must ≥18 years of age
- Previously untreated AML (de novo or secondary) defined according to World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL) [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation scheduled for induction therapy followed by consolidation therapy. Participants with secondary AML is defined as AML arising after myelodysplastic syndromes (MDSs) or other antecedent hematologic disorders (AHDs) or AML arising after exposure to genotoxic injury including radiation and/or chemotherapy are also eligible. Participants may have had previous treatment for MDS or other AHD, including hypomethylating agents (HMAs), provided it was ≥ 14 days prior to study drug initiation
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 2
- 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 (only for patients who will be receiving AG-221), or leukemic involvement following approval by the study Sponsor; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic involvement following approval by the study Sponsor
- Adequate renal function as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance 40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)
- Agree to serial blood and bone marrow sampling
- Meet any criteria necessary for the safe and proper use of the induction and consolidation agents involved in this trial
- Able to understand and willing to sign an informed consent form. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to, and approved by, the site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
- Female participants with reproductive potential must agree to undergo a 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). A pregnancy test should also be performed on the day of the first study drug administration and confirmed negative prior to dosing as well as before dosing on Day 1 of all subsequent cycles
- Female participants with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of the therapy. Participants 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 for at least 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 one highly effective form (for participants receiving AG-221) or two highly effective forms (for participants receiving AG-120) of contraception from the time of giving informed consent, during the study, and for 2 months (for participants receiving AG-221) and for 4 months (for participants receiving AG-120) following the last dose of AG-120 or AG-221 (females and males). 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
Exclusion Criteria:
- Prior chemotherapy for AML. Hydroxyurea is allowed prior to enrollment for the control of peripheral leukemic blasts in participants with leukocytosis; hydroxyurea may be allowed on study with study Sponsor approval
- Taking medications with narrow therapeutic windows, unless they can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study
- Taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred to other medications prior to enrolling. For participants taking AG-120, systemic administration of a moderate or strong CYP3A4 inhibitor requires careful monitoring of the heart rate-corrected QT interval (QTc) using Fridericia's formula (QTcF)
- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) or OATP1B1/1B3 transporter-sensitive substrate medications unless they can be transferred to alternative medications within ≥5 half-lives prior to administration of AG-221, or unless the medications can be adequately monitored during the study. There are no restrictions regarding the co-administration of such medications with AG-120.
- Pregnant or breastfeeding
- Uncontrolled active infection or uncontrolled invasive fungal infection (positive blood or tissue culture). An infection controlled with an approved or closely monitored antibiotic/antifungal treatment is allowed
- Prior history of malignancy, other than MDS or AML, unless the participant has been free of the disease for ≥1 year prior to the start of study treatment However, participants with the following history/concurrent conditions are allowed: basal or squamous cell carcinoma of the skin; carcinoma in situ of the cervix; carcinoma in situ of the breast; incidental histologic finding of prostate cancer
- Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction, unstable angina and/or stroke; or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO), or by other methods according to institutional practice, obtained within 28 days prior to the start of study treatment
- QTc interval using Fridericia's formula (QTcF) ≥450 milliseconds (msec) or other factors that increase the risk of QT interval prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and prolonged QTc are permitted with approval of the study Sponsor
- 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 (If equivalent medication is not available QTc will be closely monitored)
- Known infection caused by human immunodeficiency virus (HIV) or active hepatitis B or C
- Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
- Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is required only if there is a clinical suspicion of CNS involvement by leukemia during screening.
- Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
- Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a participant's ability to give informed consent or participate in the study
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: AG-120 with cytarabine and daunorubicin
Daily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-120.
Participants who complete consolidation therapy and are in complete response (CR) or complete remission with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]) may continue on maintenance therapy and receive daily treatment with AG-120.
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Experimental: AG-120 with cytarabine and idarubicin
Daily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-120.
Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-120.
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Experimental: AG-221 with cytarabine and daunorubicin
Daily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221.
Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
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Experimental: AG-221 with cytarabine and idarubicin
Daily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221.
Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
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Experimental: AG-221 (starting on Day 8) with cytarabine and daunorubicin
Daily AG-221 administered orally starting on Day 8 of induction cycle 1 in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221.
Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
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Experimental: AG-221 (starting on Day 8) with cytarabine and idarubicin
Daily AG-221 administered orally starting on Day 8 of induction cycle 1 in combination with standard Induction therapy and consolidation therapy.
After 1 cycle of induction therapy, participants may undergo a second induction cycle given as per institutional practice.
Participants who achieve an adequate response at the end of induction therapy will go on to receive consolidation therapy (mitoxantrone/etoposide or up to 4 cycles of cytarabine) in combination with AG-221.
Participants who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Percentage of Participants with Adverse Events (AEs)
Time Frame: Up to 26 weeks
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An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.
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Up to 26 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Recommended Phase 2 Dose (RP2D) of AG-120 and AG-221 when Administered with Induction and Consolidation Therapy
Time Frame: Up to 26 weeks
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Up to 26 weeks
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Pharmacokinetics (PK) of AG-120 and AG-221 in Plasma when Administered with Induction and Consolidation Therapy
Time Frame: Up to 26 weeks
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Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population.
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Up to 26 weeks
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2-hydroxyglutarate (2-HG) Levels in Plasma
Time Frame: Up to 26 weeks
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Up to 26 weeks
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Clinical Activity of AG-120 and AG-221 According to the 2003 Revised International Working Group (IWG) Criteria for AML
Time Frame: Up to 26 weeks
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Up to 26 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Fan B, Chen Y, Yin F, Hua L, Almon C, Nabhan S, Cooper M, Yang H, Hossain M. Pharmacokinetic/Pharmacodynamic Evaluation of Ivosidenib or Enasidenib Combined With Intensive Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed IDH1/2-Mutant Acute Myeloid Leukemia. Clin Pharmacol Drug Dev. 2022 Apr;11(4):429-441. doi: 10.1002/cpdd.1067. Epub 2022 Feb 14.
- Stein EM, DiNardo CD, Fathi AT, Mims AS, Pratz KW, Savona MR, Stein AS, Stone RM, Winer ES, Seet CS, Dohner H, Pollyea DA, McCloskey JK, Odenike O, Lowenberg B, Ossenkoppele GJ, Patel PA, Roshal M, Frattini MG, Lersch F, Franovic A, Nabhan S, Fan B, Choe S, Wang H, Wu B, Hua L, Almon C, Cooper M, Kantarjian HM, Tallman MS. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood. 2021 Apr 1;137(13):1792-1803. doi: 10.1182/blood.2020007233.
- Shallis RM, Podoltsev NA. Maintenance therapy for acute myeloid leukemia: sustaining the pursuit for sustained remission. Curr Opin Hematol. 2021 Mar 1;28(2):110-121. doi: 10.1097/MOH.0000000000000637.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
December 31, 2015
Primary Completion (Actual)
December 13, 2018
Study Completion (Estimated)
July 1, 2024
Study Registration Dates
First Submitted
November 19, 2015
First Submitted That Met QC Criteria
December 14, 2015
First Posted (Estimated)
December 17, 2015
Study Record Updates
Last Update Posted (Actual)
October 11, 2023
Last Update Submitted That Met QC Criteria
October 10, 2023
Last Verified
October 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Bone Marrow Diseases
- Precancerous Conditions
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Preleukemia
- Hematologic Diseases
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antibiotics, Antineoplastic
- Etoposide
- Cytarabine
- Daunorubicin
- Idarubicin
- Mitoxantrone
Other Study ID Numbers
- AG120-221-C-001
- 2015-004290-33 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
YES
IPD Plan Description
Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.
Access can be requested for all interventional clinical studies:
- used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
- where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.
In addition, access can be requested for all interventional clinical studies in patients:
- sponsored by Servier
- with a first patient enrolled as of 1 January 2004 onwards
- for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.
IPD Sharing Time Frame
After Marketing Authorisation in EEA or US if the study is used for the approval.
IPD Sharing Access Criteria
Researchers should register on Servier Data Portal and fill in the research proposal form.
This form in four parts should be fully documented.
The Research Proposal Form will not be reviewed until all mandatory fields are completed.
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
- CSR
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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