Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation
Condition: Newly Diagnosed Acute Myeloid Leukemia (AML); Untreated AML; AML Arising From Myelodysplastic Syndrome (MDS); Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes
Intervention: AG-120; Placebo; Azacitidine
Intervention description: Tablets administered orally; Tablets administered orally; Administered SC or IV
Intervention MeSH terms: Azacitidine; Ivosidenib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 146.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia; Leukemia; Azacitidine; AG-120; ivosidenib

Summary:

      Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized,
      placebo-controlled clinical trial to evaluate the efficacy and safety of AG-120 (ivosidenib)
      + azacitidine vs placebo + azacitidine in adult participants with previously untreated IDH1m
      AML who are considered appropriate candidates for non-intensive therapy. The primary endpoint
      is event-free survival (EFS). The key secondary efficacy endpoints are overall survival (OS),
      rate of complete remission (CR), rate of CR and complete remission with partial hematologic
      recovery (CRh), and overall response rate (ORR). Participants eligible for study treatment
      based on Screening assessments will be randomized 1:1 to receive oral AG-120 or matched
      placebo, both administered in combination with subcutaneous (SC) or intravenous (IV)
      azacitidine. An estimated 200 participants will take part in the study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Be ≥ 18 years of age and meet at least 1 of the following criteria defining
             ineligibility for intensive induction chemotherapy (IC): ≥ 75 years old, Eastern
             Cooperative Oncology Group Performance Status (ECOG PS) score of 2, severe cardiac
             disorder (e.g., congestive heart failure requiring treatment, left ventricular
             ejection fraction (LVEF), ≤50%, or chronic stable angina), severe pulmonary disorder
             (e.g., diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory
             volume in 1 second ≤65%), creatinine clearance <45 mL/minute, bilirubin >1.5 times the
             upper limit of normal (ULN) and/or have any other comorbidity that the Investigator
             judges to be incompatible with intensive IC and must be reviewed and approved by the
             Medical Monitor before study enrollment.

          2. Have previously untreated AML, defined according to World Health Organization (WHO)
             criteria, with ≥ 20% leukemic blasts in the bone marrow. Participants with
             extramedullary disease alone (i.e., no detectable bone marrow and no detectable
             peripheral blood AML) are not eligible for the study.

          3. Have an isocitrate dehydrogenase 1 (IDH1) mutation.

          4. Have an ECOG PS score of 0 to 2.

          5. Have adequate hepatic function.

          6. Have adequate renal function.

          7. Have agreed to undergo serial blood and bone marrow sampling.

          8. Be able to understand and willing to sign an informed consent form (ICF).

          9. Be willing to complete Quality of Life assessments during the study

         10. If female with reproductive potential, must have a negative serum pregnancy test prior
             to the start of study therapy. Females of reproductive potential, as well as fertile
             men and their female partners of reproductive potential, must agree to use 2 effective
             forms of contraception.

        Exclusion Criteria:

          1. Are candidates for and willing to receive intensive induction chemotherapy (IC) for
             their AML.

          2. Have received any prior treatment for AML with the exception of hydroxyurea.

          3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).

          4. Participants who had previously received an experimental agent for MDS may not be
             randomized until a washout period has elapsed since the last dose of that agent.

          5. Have received prior treatment with an IDH1 inhibitor.

          6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or
             azacitidine.

          7. Are female and pregnant or breastfeeding.

          8. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without
             improvement despite appropriate antibiotics, antiviral therapy, and/or other
             treatment.

          9. Have a prior history of cancer other than MDS or myeloproliferative disorder, unless
             the participant has been free of the disease for ≥ 1 year prior to the start of study
             treatment.

         10. Have had significant active cardiac disease within 6 months prior to the start of the
             study treatment.

         11. Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia.

         12. Have a condition that limits the ingestion or absorption of drugs administered by
             mouth.

         13. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic
             BP > 100 mmHg).

         14. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or
             known CNS leukemia.

         15. Have immediate, life-threatening, severe complications of leukemia, such as
             uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated
             intravascular coagulation.

         16. Have any other medical or psychological condition deemed by the Investigator to be
             likely to interfere with the participant's ability to give informed consent or
             participate in the study.

         17. Are 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, or unless the
             medications can be properly monitored during the study. (If equivalent medication is
             not available, heart rate corrected QT interval [QTc] will be closely monitored.)

         18. Have a known medical history of progressive multifocal leukoencephalopathy.