A Study of CPX-351 (Vyxeos™) With Quizartinib for the Treatment of FLT3-ITD Mutation-Positive Acute Myeloid Leukemia
Condition: Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: CPX-351; Quizartinib
Intervention description: Given during the induction and consildation phase and will consist of 44 mg/m^2 daunorubicin with 100 mg/m^2 cytarabine administered intravenously on Days 1, 3, and 5 during induction phase and Days 1 and 3 of consolidation phase.; Given during induction, consolidation, and maintenance phases and will be taken orally at a dose of 30mg on Days 8-21 of induction phase, Days 6-21 of consolidation phase, and daily in maintenance phase.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: FLT3

Summary:

      This is a research study to be done at multiple sites in participants with advanced acute
      myeloid leukemia (AML) that have a mutation in Fms-like tyrosine kinase-3 internal tandem
      duplications (FLT3-ITD). This study is to learn more about an investigational drug,
      quizartinib, being tested with the anti-cancer medicine CPX-351 (also called Vyxeos™), which
      is approved and widely used to treat AML.

      The purpose of this study is to assess the safety, tolerability and survival of patients
      receiving the combination of CPX-351 and quizartinib.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent form (ICF), according to local guidelines, signed by the
             patient or by a legal guardian prior to the performance of any study-related screening
             procedures.

          2. Patients with the following types of AML with >5% blasts:

               -  Relapsed FLT3-ITD mutation-positive AML, diagnosed by bone marrow (BM) biopsy
                  with FLT3 mutation by polymerase chain reaction (PCR)

               -  Refractory FLT3-ITD mutation-positive AML, diagnosed by BM biopsy with FLT3
                  mutation by PCR

               -  Relapsed or refractory FLT3-ITD mutation-positive AML after HCT, diagnosed by BM
                  biopsy with FLT3 mutation by PCR

               -  Relapsed or refractory AML with de novo FLT3-ITD mutation, diagnosed by BM biopsy
                  with FLT3 mutation by PCR

               -  Relapsed or refractory AML after HCT with de novo FLT3-ITD mutation, diagnosed by
                  BM biopsy with FLT3 mutation by PCR

          3. First-line therapy must have contained a standard induction chemotherapy (e.g. 7+3,
             FLAG-IDA, FLAG, CLAG, MEC, hypomethylating agent with venetoclax) with or without
             receiving a prior FLT3 inhibitor (e.g. midostaurin) or multi-tyrosine kinase inhibitor
             (e.g. sorafenib). All patients who relapsed after an alloHCT are included, except
             patients with active graft-versus-host disease (GVHD) requiring >10 mg prednisone.

          4. Patients must be able to swallow and retain oral medication.

          5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2
             (Appendix A).

          6. Adequate renal and hepatic parameters (aspartate aminotransferase [AST], alanine
             aminotransferase [ALT] ≤2.5 institutional upper limit of normal [ULN]; total bilirubin
             ≤2.0 institutional ULN; serum creatinine [Cr] ≤2.0). In patients with suspected liver
             infiltration, ALT can be ≤5 institutional ULN.

        Exclusion Criteria:

          1. Acute promyelocytic leukemia (t[15;17])

          2. Female patients who are lactating or have a positive serum pregnancy test during the
             screening period. Female patients of childbearing potential who are not willing to
             employ highly effective birth control (as defined in Appendix C of protocol) from
             screening to 6 months following the last dose of CPX-351 and/or quizartinib.

          3. Evidence of active and uncontrolled bacterial, fungal, parasitic, or viral infection.
             Infections are considered controlled if appropriate therapy has been instituted and,
             at the time of screening, no signs of active infection progression are present. This
             is assessed by the site clinicians, including an infectious disease consulting
             physician, if requested by the Principal Investigator (PI), regarding adequacy of
             therapy. These infections include, but are not limited to:

               -  Known human immunodeficiency virus (HIV) infection

               -  Active hepatitis B or C infection with rising transaminase values

               -  Active tuberculosis infection

          4. History of hypersensitivity to cytarabine, daunorubicin, or an FLT3 inhibitor

          5. Any patients with known significant impairment in gastrointestinal (GI) function or GI
             disease that my significantly alter the absorption of quizartinib.

          6. Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.

          7. Uncontrolled or significant cardiovascular disease, including any of the following:

               -  Bradycardia of less than 50 beats per minute, unless the patient has a pacemaker

               -  QTcF interval using Fridericia's correction factor (QTcF) interval prolongation,
                  defined as >450msec at screening and prior to first administration of quizartinib

               -  Diagnosis of or suspicion of long QT syndrome (including family history of long
                  QT syndrome)

               -  Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg

               -  History of clinically relevant ventricular arrhythmias (i.e., ventricular
                  tachycardia, ventricular fibrillation or Torsades de pointes)

               -  History of second or third degree heart block without a pacemaker

               -  Right bundle branch and left anterior hemiblock (bifascicular block), complete
                  left bundle branch block

               -  Ejection fraction <50% by transthoracic echocardiogram (TTE) or multigated
                  acquisition (MUGA) scan

               -  History of uncontrolled angina pectoris or myocardial infarction within 6 months
                  prior to Screening

          8. History of New York Heart Association Class 3 or 4 heart failure

          9. Prior anthracycline (or equivalent) cumulative exposure ≥368 mg/m2 daunorubicin (or
             equivalent)

         10. Any serious underlying medical condition that, in the opinion of the Investigator or
             Medical Monitor, would impair the ability to receive or tolerate the planned
             treatment.

         11. Patients with inadequate adequate pulmonary function will be excluded. Inadequate
             pulmonary function is defined as requiring supplemental O2, or diffusing capacity of
             the lungs for carbon monoxide [DLCO] <40%.

         12. Active acute or chronic GVHD requiring prednisone >10 mg or equivalent.