Clinical Trials /

An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation

NCT02577406

Description:

This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
  • Official Title: A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation

Clinical Trial IDs

  • ORG STUDY ID: AG-221-AML-004
  • NCT ID: NCT02577406

Conditions

  • Leukemia, Myeloid
  • Isocitrate Dehydrogenase

Interventions

DrugSynonymsArms
AG-221AG-221 plus Best supportive care (BSC)
AzacitidineConventional care regimen (CCR)
Low-dose cytarabine (LDAC)Conventional care regimen (CCR)
Intermediate-dose cytarabine (IDAC)Conventional care regimen (CCR)

Purpose

This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.

Detailed Description

      Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations
      in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of
      patients with AML.

      The outcome of first line chemotherapy treatment is poor and many patients fail to attain
      complete remission (CR, ie refractory) or will eventually relapse. There is no single
      standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a
      great need for new therapies.

      Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML.
      AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target
      the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be
      generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed
      or refractory AML.

      The study purpose is to test the safety and efficacy of AG-221 compared with conventional
      care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC,
      low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late
      stage AML refractory to or relapsed after second or third line therapy and positive for the
      IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or
      one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78
      months which includes 42 months enrollment, approximately 7 months treatment and a follow-up
      period.

      Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone
      marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment
      response. Bone marrow, blood, cheek swab samples will be used for genetic tests.

      This study is being sponsored by Celgene Corporation. Approximately 316 participants will
      take part in the study.
    

Trial Arms

NameTypeDescriptionInterventions
AG-221 plus Best supportive care (BSC)ExperimentalContinuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.
  • AG-221
Conventional care regimen (CCR)Active ComparatorContinuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
  • Azacitidine
  • Low-dose cytarabine (LDAC)
  • Intermediate-dose cytarabine (IDAC)

Eligibility Criteria

        Inclusion Criteria:

        Subjects must satisfy the following criteria to be enrolled in the study:

          1. Subject is ≥ 60 years of age at the time of signing the ICF

          2. Subject has primary (ie, de novo) or secondary (progression of MDS or
             myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO
             classification (Appendix B)

          3. Subject has received second- or third-line of AML therapy (see Appendix G for the
             definition of prior AML line; note that, for subjects having AML secondary to prior
             higher risk [Intermediate-2 or High risk according to the International Prognostic
             Scoring System] MDS treated with a hypomethylating agent [eg, azacitidine or
             decitabine], the hypomethylating therapy can be counted as a line if there is disease
             progression to AML during or shortly [eg, within 60 days] after the hypomethylating
             therapy.)

          4. Subject has the following disease status:

               1. Refractory to or relapsed after second- or third-line of intensive therapy for
                  AML (eg, the "7 + 3" regimen):

                  at least 5% leukemic blasts in bone marrow (the minimum number of treatment
                  cycles of the intensive therapy is per the investigator's discretion); or

               2. Refractory to or relapsed after second- or third-line low-intensity AML therapy
                  (eg, LDAC, azacitidine or decitabine):

             at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles

          5. Subject is eligible for and willing to receive the pre-selected CCR treatment option,
             according to the investigator's assessment (Note: Subjects with degenerative and toxic
             encephalopathies, especially after the use of methotrexate or treatment with ionizing
             radiation, should not receive cytarabine.)

          6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
             (Appendix D)

          7. Subject has IDH2 gene mutations tested centrally (using the "investigational use
             only"PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and
             peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral
             blood. (Note: in the event that the central laboratory result is delayed and precludes
             acute clinical management of a subject who has confirmed IDH2 gene mutation by local
             evaluation, the subject may be eligible for randomization with approval by the Medical
             Monitor.)

          8. Subject has adequate organ function defined as:

               -  Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
                  and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3
                  x upper limit of normal (ULN), unless considered due to leukemic organ
                  involvement, following review by the Medical Monitor; and

               -  Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome
                  (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review
                  by the Medical Monitor; and

               -  Creatinine clearance > 30 mL/min based on the Modification of Diet in Renal
                  Disease (MDRD) glomerular filtration rate (GFR):

             GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 if
             female) × (1.212 if African American)

          9. Females of childbearing potential (FCBP)* may participate, providing they meet the
             following conditions:

               -  Agree to practice true abstinence from sexual intercourse or to use highly
                  effective contraceptive methods (eg, combined [containing estrogen and
                  progestogen] or progestogen-only associated with inhibition of ovulation, oral,
                  injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral
                  tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or
                  male partner sterilization [note that vasectomized partner is a highly effective
                  birth control method provided that partner is the sole sexual partner of the FCBP
                  trial participant and that the vasectomized partner has received medical
                  assessment of the surgical success]) at screening and throughout the study, and
                  for 4 months following the last study treatment (6 months following the last dose
                  of cytarabine); and

               -  Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy
                  test (sensitivity of at least 25 mIU/mL) at screening; and

               -  Have a negative serum or urine (investigator's discretion under local
                  regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72
                  hours prior to the start of study treatment in the Treatment Phase (note that the
                  screening serum pregnancy test can be used as the test prior to the start of
                  study treatment in the Treatment Phase if it is performed within the 72-hour
                  timeframe).

         10. Male subjects must agree to practice true abstinence from sexual intercourse or to the
             use of highly effective contraceptive methods (as described above) with non-pregnant
             female partners of childbearing potential at screening and throughout the course of
             the study, and should avoid conception with their partners during the course of the
             study and for 4 months following the last study treatment (6 months following the last
             dose of cytarabine; 6 months following the last dose of azacitidine in Canada)

         11. Subject must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted

         12. Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment:

          1. Subject is suspected or proven to have acute promyelocytic leukemia based on
             morphology, immunophenotype, molecular assay, or karyotype

          2. Subject has AML secondary to chronic myelogenous leukemia

          3. Subject has received a targeted agent against an IDH2 mutation

          4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to
             the start of study treatment. Note that hydroxyurea is allowed prior to the start of
             study treatment for the control of leukocytosis (however, hydroxyurea should not be
             given within 72 hours prior to and after administration of azacitidine).

          5. Subject has received non-cytotoxic or investigational agents < 14 days or 5
             half-lives, whichever is longer, prior to the start of study treatment

          6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or 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 steroid
             post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.

          7. Subject has persistent, clinically significant non-hematologic toxicities from prior
             therapies

          8. Subject has or is suspected of having central nervous system (CNS) leukemia.
             Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
             suspected during screening.

          9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection
             (defined as ongoing signs/symptoms related to the infection without improvement
             despite appropriate antibiotics, antiviral therapy, and/or other treatment)

         10. Subject has immediately life-threatening, severe complications of leukemia such as
             uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
             intravascular coagulation

         11. Subject has 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 (Appendix E); acute coronary syndrome (ACS); and/or stroke;
             or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or
             multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of
             study treatment

         12. Subject has prior history of malignancy, other than MDS, MPN 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 (T1a or T1b using the tumor,
                  node, metastasis clinical staging system)

         13. Subject is known seropositive or active infection with human immunodeficiency virus
             (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

         14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
             conditions that limit the ingestion or gastrointestinal absorption of drugs
             administered orally

         15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
             diastolic BP > 100 mmHg)

         16. Subject is a pregnant or lactating female

         17. Subject has known or suspected to have hypersensitivity to any of the components of
             study treatment

         18. Subject is taking those medications (listed in Section 8.2) that are known to prolong
             QT interval unless the subject can be transferred to other medications at least 5
             half-lives prior to the start of study treatment

         19. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or other
             factors that increase the risk of QT prolongation or arrhythmic events (eg, heart
             failure, hypokalemia, family history of long QT interval syndrome) at screening

         20. Subject is taking the following sensitive CYP substrate medications that have a narrow
             therapeutic range are excluded from the study unless the subject can be transferred to
             other medications at least 5 half-lives prior to the start of study treatment:
             paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19),
             thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)

         21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
             substrate rosuvastatin should be excluded from the study unless the subject can be
             transferred to other medications at least 5 half-lives prior to the start of study
             treatment

         22. Subject has any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study

         23. Subject has any condition including the presence of laboratory abnormalities, which
             places the subject at unacceptable risk if he/she were to participate in the study

         24. Subject has any condition that confounds the ability to interpret data from the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Time from randomization to death due to any cause

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to approximately 49 months
Safety Issue:
Description:The rate of morphologic leukemia-free state (MLFS) + Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Measure:Event-free survival
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Time from randomization to documented morphologic relapse, PD according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria or death from any cause, whichever occurs first
Measure:Duration of response
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, Progressive disease (PD) according to modified IWG AML response criteria or death due to any cause, whichever occurs first
Measure:Time to response
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Time from randomization to first documented MLFS/CR/CRi/CRp/PR according to modified IWG AML response criteria
Measure:Treatment mortality at 30 and 60 days
Time Frame:At 30 and 60 days after treatment start
Safety Issue:
Description:Rate of death from any cause within 30 and 60 days of initiation of study treatment
Measure:One-year survival
Time Frame:Up to approximately 49 months
Safety Issue:
Description:The probability of survival at 1 year from randomization
Measure:Overall remission rate
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Rate of CR + CRi + CRp according to modified IWG AML response criteria
Measure:Complete remission rate
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Rate of CR according to modified IWG AML response criteria
Measure:Hematologic improvement rate
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Rate of Hematologic improvement neutrophil response (HI-N) + Hematologic improvement platelet response (HI-P) + Hematologic improvement erythroid response (HI-E) according to International Working Group (IWG) Myelodysplastic syndromes (MDS) Hematologic improvement (HI) criteria
Measure:Rate of Hematopoietic stem cell transplantation (HSCT)
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Rate of bridge-to-HSCT through study treatment
Measure:Time to treatment failure
Time Frame:Up to approximately 49 months
Safety Issue:
Description:Time from randomization to discontinuation of study treatment due to any cause response criteria or death due to any cause, whichever occurs first
Measure:Adverse Events (AEs)
Time Frame:Up to approximately 78 months
Safety Issue:
Description:Number of participants with adverse events
Measure:European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30)
Time Frame:Up to approximately 49 months
Safety Issue:
Description:A validated quality of life measure applicable to subjects with any cancer diagnosis. .
Measure:EuroQoL Group EQ-5D-5L Health Questionnaire
Time Frame:Up to approximately 49 months
Safety Issue:
Description:A standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status, and is applicable to a wide range of health conditions and treatments.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • AG-221
  • CC-90007
  • Efficacy
  • Safety
  • Leukemia
  • Acute myeloid meukemia
  • Isocitrate dehydrogenase 2 mutation
  • Enasidenib

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