(QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive
Condition: AML
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Quizartinib; Salvage Chemotherapy
Intervention description: 20 or 30 mg quizartinib tablets administered orally once daily; Low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA) administered during 28-day cycles
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 367.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia; AML; FMS-like tyrosine kinase 3; FLT3-ITD; Quizartinib; Leukemia; Tablets

Summary:

      The primary objective of the study is to determine whether quizartinib monotherapy prolongs
      overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine
      kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have
      relapsed within 6 months, after first-line AML therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of written informed consent approved by the Institutional Review Board (IRB)
             or Independent Ethics Committee (IEC) with privacy language in accordance with
             national regulations (e.g., Health Insurance Portability and Accountability Act
             [HIPAA] authorization for United States [US] sites) prior to any study related
             procedures, including withdrawal of prohibited medications if applicable.

          2. Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of
             Informed consent.

          3. Morphologically documented primary Acute Myeloid Leukemia (AML) or AML secondary to
             Myelodysplastic Syndrome (MDS), as defined by World Health Organization (WHO)
             criteria, as determined by pathology review at the study site.

          4. In first relapse (with duration of remission of 6 months or less) or refractory after
             prior therapy, with or without HSCT. Induction therapy must have included at least 1
             cycle of an anthracycline/mitoxantrone-containing induction block at a standard dose.

          5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood
             (allelic ratio as determined by a central laboratory with a cutoff of ≥3%
             FLT3-ITD/total FLT3). If a specimen has been sent for FLT3-ITD testing at the central
             laboratory but the subject requires treatment for AML before the central FLT3-ITD test
             result is available, a local test result may be acceptable for randomization after
             consultation with the Medical Monitor.

          6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator's
             assessment.

          7. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.

          8. Discontinuation of prior AML treatment before the start of study treatment (except
             hydroxyurea or other treatment to control leukocytosis) for at least 2 weeks for
             cytotoxic agents, or for at least 5 half-lives for non cytotoxic agents.

          9. Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate >25
             mL/min, as calculated with the Cockcroft-Gault formula.

         10. Serum potassium, magnesium, and calcium (serum calcium corrected for hypoalbuminemia)
             within institutional normal limits. Subjects with electrolytes outside the normal
             range will be eligible if these values are corrected upon retesting following any
             necessary supplementation.

         11. Total serum bilirubin ≤1.5×ULN.

         12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN.

        Exclusion Criteria:

          1. Acute Promyelocytic Leukemia (AML subtype M3).

          2. AML secondary to prior chemotherapy for other neoplasms, except AML secondary to prior
             Myelodysplastic Syndrome (MDS).

          3. History of another malignancy, unless the candidate has been disease-free for at least
             5 years.

          4. Persistent, clinically significant > Grade 1 non-hematologic toxicity from prior AML
             therapy.

          5. Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation
             of treatment or treatment escalation within 21 days, and/or > Grade 1 persistent or
             clinically significant non hematologic toxicity related to HSCT.

          6. History of or current, central nervous system involvement with AML.

          7. Clinically significant coagulation abnormality, such as disseminated intravascular
             coagulation.

          8. Prior treatment with quizartinib or participated in a prior quizartinib study.

          9. Prior treatment with a FLT3 targeted therapy including sorafenib or investigational
             FLT3 inhibitors (not including the multi-kinase inhibitor, midostaurin).

         10. Major surgery within 4 weeks prior to screening.

         11. Radiation therapy within 4 weeks prior to screening.

         12. Uncontrolled or significant cardiovascular disease

         13. Active infection not well controlled by antibacterial or antiviral therapy.

         14. Known infection with human immunodeficiency virus, or active hepatitis B or C, or
             other active clinically relevant liver disease.

         15. Unwillingness to receive infusion of blood products according to the protocol.

         16. In a man whose sexual partner is a woman of childbearing potential, unwillingness or
             inability of the man or woman to use a highly effective contraceptive method for the
             entire study treatment period for at least 3 months after study completion. Male
             subjects must not freeze or donate sperm starting at Screening and throughout the
             study period, and 105 days after the final study drug administration.

         17. In a heterosexually active woman of childbearing potential, unwillingness or inability
             to use a highly effective contraceptive method for the entire study treatment period
             and for at least 3 months after study treatment completion. Additionally, for women
             randomized to chemotherapy, unwillingness to adhere to the restrictions in the
             respective locally established guidelines and local approved label (prescribing
             information, Summary of Product Characteristics, or US product insert) from the
             manufacturer and the Patient Information Leaflet (package insert) as instructed by the
             Investigator.

         18. Pregnancy.

         19. Female Subjects must agree to not breastfeed from the time of Screening and throughout
             the study period, and for 25 days after the final study drug administration.

         20. Medical condition, serious intercurrent illness, or other circumstance that, in the
             Investigator's judgment, could jeopardize the candidate's safety as a study subject,
             or that could interfere with study objectives.

         21. For subjects in the United Kingdom only: Refusal of permission to allow the subject's
             General Practitioner to be notified of their participation in the study.