Clinical Trials /

Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

NCT02632708

Description:

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 1 dose level of AG-120 in subjects with an IDH1 mutation and 1 dose level (and 2 dose schedules) of AG-221 in subjects with an 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, subjects may continue on to maintenance therapy and receive daily treatment of AG-120 or AG-221 until the end of study or until relapse, development of an unacceptable toxicity, or hematopoietic stem cell transplant (HSCT). End of study is defined as 2 years from the time the last subject enrolls, or sooner, if all subjects have come off study (or withdrew consent) prior to 2 years after the last subject has enrolled.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: AG120-221-C-001
  • NCT ID: NCT02632708

Conditions

  • Newly Diagnosed Acute Myeloid Leukemia (AML)
  • Untreated AML
  • AML Arising From Myelodysplastic Syndrome (MDS)
  • AML Arising From Antecedent Hematologic Disorder (AHD)
  • AML Arising After Exposure to Genotoxic Injury

Interventions

DrugSynonymsArms
AG-120AG-120 with cytarabine and daunorubicin
AG-221AG-221 with cytarabine and daunorubicin
cytarabineAG-120 with cytarabine and daunorubicin
daunorubicinAG-120 with cytarabine and daunorubicin
idarubicinAG-120 with cytarabine and idarubicin
mitoxantroneAG-120 with cytarabine and daunorubicin
etoposideAG-120 with cytarabine and daunorubicin

Purpose

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 1 dose level of AG-120 in subjects with an IDH1 mutation and 1 dose level (and 2 dose schedules) of AG-221 in subjects with an 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, subjects may continue on to maintenance therapy and receive daily treatment of AG-120 or AG-221 until the end of study or until relapse, development of an unacceptable toxicity, or hematopoietic stem cell transplant (HSCT). End of study is defined as 2 years from the time the last subject enrolls, or sooner, if all subjects have come off study (or withdrew consent) prior to 2 years after the last subject has enrolled.

Trial Arms

NameTypeDescriptionInterventions
AG-120 with cytarabine and daunorubicinExperimentalDaily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-120.
  • AG-120
  • cytarabine
  • daunorubicin
  • mitoxantrone
  • etoposide
AG-120 with cytarabine and idarubicinExperimentalDaily AG-120 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-120.
  • AG-120
  • cytarabine
  • idarubicin
  • mitoxantrone
  • etoposide
AG-221 with cytarabine and daunorubicinExperimentalDaily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
  • AG-221
  • cytarabine
  • daunorubicin
  • mitoxantrone
  • etoposide
AG-221 (starting on Day 8) with cytarabine and idarubicinExperimentalDaily AG-221 administered orally in combination with standard Induction therapy and consolidation therapy. After 1 cycle of induction therapy, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
  • AG-221
  • cytarabine
  • idarubicin
  • mitoxantrone
  • etoposide
AG-221 (starting on Day 8) with cytarabine and daunorubicinExperimentalDaily 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, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
  • AG-221
  • cytarabine
  • daunorubicin
  • mitoxantrone
  • etoposide
AG-221 with cytarabine and idarubicinExperimentalDaily 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, subjects may undergo a second induction cycle given as per institutional practice. Subjects 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. Subjects who complete consolidation therapy and are in CR or CRi (including CRp) may continue on maintenance therapy and receive daily treatment with AG-221.
  • AG-221
  • cytarabine
  • idarubicin
  • mitoxantrone
  • etoposide

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must ≥18 years of age

          -  Previously untreated AML (de novo or secondary) defined according to World Health
             Organization (WHO) criteria, excluding APL [AML with t(15;17)], with locally
             documented IDH1 and/or IDH2 gene mutation scheduled for induction therapy followed by
             consolidation therapy. 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. Subjects may
             have had previous treatment for MDS or other AHD, including hypomethylating agents
             (HMAs), provided that the last dose of administration is ≥ 14 days prior to study drug
             initiation

          -  ECOG PS score of 0 to 2

          -  Adequate hepatic function as evidenced by: serum total bilirubin ≤1.5 × 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 subject 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 subjects 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 subjects with reproductive potential must have a negative serum pregnancy test
             within 7 days prior to the start of the 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 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 two highly effective forms of contraception from the time
             of giving informed consent, during the study, and for 4 months (females and males)
             following the last dose of AG-120 or 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

        Exclusion Criteria:

          -  Prior chemotherapy for AML. Hydroxyurea is allowed for the control of peripheral
             leukemic blasts in subjects with leukocytosis

          -  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 subjects 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 subject has been free
             of the disease for ≥1 year prior to the start of study treatment However, subjects
             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 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 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 subject's ability to give informed consent or participate in the
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/tolerability of AG-120 and AG-221 when administered with induction and consolidation therapy: incidence of adverse events
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Establish the recommended Phase 2 dose (RP2D) of AG-120 and AG-221 when administered with induction and consolidation therapy
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure:Pharmacokinetics of AG-120 and AG-221 in plasma when administered with induction and consolidation therapy
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population.
Measure:2-hydroxyglutarate (2-HG) levels in plasma
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure: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, on average
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Agios Pharmaceuticals, Inc.

Trial Keywords

  • Acute Myeloid Leukemia
  • AML
  • Untreated AML
  • De novo AML
  • Secondary AML
  • Newly diagnosed AML
  • IDH1
  • IDH2
  • Induction therapy
  • Consolidation therapy
  • IDH

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