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A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML)

NCT02677922

Description:

This Phase 1b/2 study is an open-label, randomized, multicenter trial to evaluate the safety and efficacy of oral AG-120 + Subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively. The study population consists of subjects who are not candidates to receive intensive Inductive chemotherapy (IC). The study comprises a Phase 1b dose-finding and AG-120 expansion stage and a Phase 2 randomized stage.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML)
  • Official Title: A Phase 1b/2 Open-label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: AG-221-AML-005
  • NCT ID: NCT02677922

Conditions

  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
AG-120Oral AG-120 + Subcutaneous (SC) azacitidine
AzacitidineOral AG-120 + Subcutaneous (SC) azacitidine
AG-221Oral AG-221 + Subcutaneous (SC) azacitidine

Purpose

This Phase 1b/2 study is an open-label, randomized, multicenter trial to evaluate the safety and efficacy of oral AG-120 + Subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively. The study population consists of subjects who are not candidates to receive intensive Inductive chemotherapy (IC). The study comprises a Phase 1b dose-finding and AG-120 expansion stage and a Phase 2 randomized stage.

Detailed Description

      The study was redesigned to expand the number of patients analyzed during the Phase 1b stage
      of the study to determine a safe and effective dose of AG-120 administered with azacitidine
      for future studies.

      The Phase 1b (AG-120 expansion) stage will evaluate the safety, tolerability, and clinical
      activity of oral AG-120 when administered with Subcutaneous azacitidine.

      The Phase 2 stage of the study will no longer include AG-120 administered with azacitidine
      (IDH1 subjects) and IDH1 patients will not longer be included in the azacitidine alone arm.
    

Trial Arms

NameTypeDescriptionInterventions
Oral AG-120 + Subcutaneous (SC) azacitidineExperimentalSubjects with an IDH1 mutation will receive AG-120 at the RP2D orally QD on Days 1-28 of each 28-day cycle + azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.
  • AG-120
  • Azacitidine
Oral AG-221 + Subcutaneous (SC) azacitidineExperimentalSubjects with an IDH2 mutation will receive AG-221 at the RP2D orally QD on Days 1-28 of each 28-day cycle + azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.
  • Azacitidine
  • AG-221
Subcutaneous (SC) azacitidineExperimentalSubjects with either an IDH1 or IDH2 mutation will receive azacitidine 75 mg/m2/day SC for 7 days of each 28-day cycle.
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

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

          1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

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

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

          4. Subject has newly diagnosed, primary (ie, de novo) or secondary (progression of MDS or
             myeloproliferative neoplasms [MPN], or therapy-related) AML according to the WHO
             classification with ≥ 20% leukemic blasts in the bone marrow: -Have an Isocitrate
             dehydrogenase 1 (IDH1) or Isocitrate dehydrogenase 2 (IDH2) gene mutation (R132, R140,
             or R172)

               -  IDH mutational status will be assessed locally; for sites without local testing
                  capabilities, a referral lab will be identified.

                    -  By the investigator's assessment who are not candidates to receive intensive
                       Inductive chemotherapy (IC).

          5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
             2.

          6. Subject has adequate organ function defined as:

               -  Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
                  (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered
                  due to leukemic organ involvement.

               -  Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be
                  attributed to ineffective erythropoiesis, 3 times the upper limit of normal for
                  Gilbert's syndrome (eg, a gene mutation in UGT1A1), or leukemic organ
                  involvement.

               -  Serum creatinine < 2 x ULN or 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 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if
             African American)

          7. Agree to serial bone marrow aspirate/biopsies.

          8. 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 a vasectomized partner is a highly
                  effective birth control method provided that partner is the sole sexual partner
                  of the FCBP trial participant and that a vasectomized partner has received
                  medical assessment of the surgical success]) at screening and throughout the
                  study, and for at least 4 months following the last study treatment; 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 Period (note that
                  the screening serum pregnancy test can be used as the test prior to the start of
                  study treatment in the Treatment Period if it is performed within the 72-hour
                  timeframe).

          9. Male subjects must agree to practice true abstinence from sexual intercourse or agree
             to the use of highly effective contraceptive methods (as described above) with
             non-pregnant female partners of child bearing 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 at least 4 months following the last study treatment (6
             months following last dose of azacitidine in Canada). Furthermore, the male subject
             must agree to use a condom while treated with azacitidine and for at least 4 months
             following the last azacitidine dose.

        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 (CML).

          3. Subject has received a targeted agent against an Isocitrate dehydrogenase 1 (IDH1) or
             Isocitrate dehydrogenase 2 (IDH2) mutation.

          4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML.

             Note: Hydroxyurea is allowed prior to enrollment for the control of peripheral
             leukemic blasts in subjects with leukocytosis. (however, hydroxyurea should not be
             given within 72 hours prior to and after administration of azacitidine). For subjects
             with secondary AML (eg, MDS or MPN) treatment for prior cancer is not exclusionary;
             full treatment information will be collected within the CRF. The use of all trans
             retinoic acid (ATRA) for suspected APL is not exclusionary provided it is discontinued
             prior to initiation of treatment in the protocol.

          5. Subject has received more than 1 cycle of prior treatment with azacitidine, or subject
             has received any prior treatment with decitabine for Myelodysplastic syndromes (MDS).

             - Clarification: Subjects with newly diagnosed Acute myeloid leukemia (AML) who are
             currently receiving their 1st cycle of azacitidine (7 days) can be screened for the
             study. On study, Cycle 1 must be started at 28 days (+/- 3 days) after initiation of
             the pre-study azacitidine.

          6. 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.

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

          8. 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; 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.

          9. Subject has prior history of malignancy, other than MDS, Myeloproliferative neoplasm
             (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)

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

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

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

         13. 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:
             phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
             tizanidine (CYP1A2).

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

         15. 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).

         16. Subject has known or suspected hypersensitivity to any of the components of study
             therapy.

         17. Subject is taking medications that are known to prolong the QT interval unless he/she
             can be transferred to other medications within ≥ 5 half-lives prior to the start of
             study treatment.

         18. Subject has Heart rate-corrected QT (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.

         19. Female subject who is pregnant or lactating.

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

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

         22. Subject has any condition that confounds the ability to interpret data from the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs)-Phase 1B
Time Frame:Up to approximately 7 months
Safety Issue:
Description:DLTs will be defined as any of the following events that commence within 28 days of the first dose of IP in a 28-day treatment cycle, constitute a change from baseline irrespective of outcome and are determined by the investigator to be related to treatment.

Secondary Outcome Measures

Measure:Overall Response Rate - Phase 1b (Ph 1b)
Time Frame:Up to approximately 13 months
Safety Issue:
Description:Rate of Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Morphologic leukemia-free state (MLFS) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Measure:Event-Free Survival - Phase 2 (Ph 2)
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Time from randomization to documented morphologic relapse, progression according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria, or death from any cause, whichever occurs first.
Measure:Adverse Events (AEs) - Ph 2
Time Frame:Up to approximately 4 years
Safety Issue:
Description:Number of participants with adverse events
Measure:Complete remission rate - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Rate of morphologic complete remission (CR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Measure:Hematologic improvement rate - Ph 2
Time Frame:Up to approximately 30 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:Duration of Response - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria, or death due to any cause, whichever occurs first
Measure:Overall Survival - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Time from randomization to death due to any cause
Measure:One-year survival- Ph 2
Time Frame:Up to approximately 12 months
Safety Issue:
Description:The probability of survival at 1 year from randomization
Measure:Pharmacokinetics- Cmax - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Maximum observed concentration in plasma
Measure:Pharmacokinetics- Tmax - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Time to maximum concentration
Measure:Pharmacokinetics- AUC - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Area under the plasma concentration‐time curve
Measure:EORTC QLQ-C30 - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Is a validated quality-of-life measure applicable to subjects with any cancer diagnosis. It is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning. Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms
Measure:EQ-5D-5L Health Questionnaire - Ph 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Is 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
Measure:Overall Response Rate - Phase 1b (Ph 2)
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Rate of Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Morphologic leukemia-free state (MLFS) +Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
Measure:Time to Response - Phase 2
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Time from first dose of study drug to first documented Morphologic complete remission (CR)/ Morphologic complete remission with incomplete neutrophil recovery (CRi)/ Morphologic complete remission with incomplete platelet recovery (CRp)/ Morphologic leukemia-free state (MLFS)/ Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Acute Myeloid Leukemia
  • Leukemia
  • Azacitidine
  • AG-120
  • AG-221

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