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The purpose of this study is to evaluate the dose-limiting toxicities (DLT) and define the maximum tolerated dose (MTD) and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG) in participants with FLT3- mutated relapsed or refractory (R/R) acute myeloid leukemia (AML).

The treatment of FLT3- mutated relapsed or refractory (R/R) is challenging. Gilteritinib, as a single agent, is the first FLT3 inhibitor to be FDA approved in the R/R setting. This phase I clinical trial will evaluate DLT/MTD and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (CLAG-M) in patients with FLT3- mutated R/R AML. This study will also evaluate the pharmacodynamics and pharmacokinetics of gilteritinib when combined with CLAG-M at specific time points. Although this combination has not been established to have superior clinical benefit in comparison to single-agent gilteritinib, the objective of this trial is to provide a possible therapeutic benefit in addition to safety and tolerability.

Inclusion Criteria:

1. Confirmed, morphologically documented AML in first or subsequent relapse or primary induction failure. The diagnosis should be documented within 28 days prior to enrollment.

   1. Relapsed AML is defined as the reappearance of leukemic blasts in the bone marrow, peripheral blood, or any extramedullary site after the attainment of a CR/CRi, detected by morphology, flow cytometry, or immunohistochemistry.
   2. Primary induction failure is defined as failure to achieve a CR or CRi after two courses of induction chemotherapy given per physician's choice or institution's guidelines.
   3. Patients with previous allogeneic hematopoietic stem cell transplantation are allowed to participate, as are prior autologous HCT.

2. Evidence of FLT3-ITD or FLT3-TKD mutations as detected by polymerase chain reaction and/or next-generation sequencing by peripheral blood and/or bone marrow samples obtained at the time of relapse. FLT3 positivity should be documented before enrollment.

3. Allowable prior therapies include: First-line AML therapy including cytarabine, anthracyclines, gemtuzumab ozogamicin, prior hypoemethylating agents with or without venetoclax and/or FLT3 inhibitors.

4. Prior clinical trial participation is allowed with a washout period of experimental drug of at least 4 weeks.

5. Prior treatment with the FLT3 inhibitor gilteritinib is allowed (must be 12 months or greater from time of eligibility screening).

6. Age ≥18 years.

7. ECOG performance status of 0 or 1; Karnofsky 70% or higher (APPENDIX A).

8. Probability of treatment-related mortality (TRM) <13.1% as calculated by performance status, age, platelet count, albumin, secondary vs primary AML, WBC count, creatinine, and percentage of peripheral blood blasts.50

   a. This score corresponds to corresponding to a ≤13.1% probability of 4-week mortality. Although this score was validated for newly diagnosed AML, it was previously used in the relapsed/refractory setting.30,51,52 (see APPENDIX B). An online calculator is available at: https://cstaging.fhcrc-research.org/TRM/).

9. Adequate organ function as defined below:

   1. Creatinine clearance (CrCl) >60 mL/min as measured by Cockcroft-Gault formula (APPENDIX C).
   2. Ejection fraction (EF) ≥ 50% as documented by an echocardiogram or multiple gated cardiac blood pool imaging (MUGA) if the echocardiogram's result is judged to be unreliable by the performing cardiologist.
   3. Total bilirubin ≤ 1.5 × the ULN, unless due to Gilbert's, hemolysis or leukemic infiltration, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN, unless caused by leukemic infiltration.

10. Female participants must be either:

    a. Of non-child bearing potential i. postmenopausal status prior to eligibility screening (defined as at least 12 consecutive months of amenorrhea), or ii. undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).

    b. Of childbearing potential. These women must agree to all of the following: i. Negative serum/urine pregnancy test at eligibility screening. ii. Abstain from pregnancy during the study and for 6 months after the final study drug administration.

    iii. If heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at eligibility screening and throughout the study period and for 6 months after the final study drug administration.

11. Female participants must agree not to breastfeed or donate ova throughout the study drug treatment period and for 6 months after the final study drug administration.

12. Male patients should agree to:

    1. Avoid impregnating a female partner, during the study and for 180 days after the final study drug administration.
    2. Avoid donating sperm during the study and for 180 days after the final study drug administration.
    3. Consistently use highly effective contraception in addition to a barrier method (even if surgically sterilized) along with their partners who are women of childbearing potential, throughout the study drug treatment period and for 6 months after the final study drug administration.

13. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. History of prior treatment with gilteritinib within the last 12 months.

2. Purine analogue (cladribine and fludarabine) treatment as part of their last line of therapy.

3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to gilteritinib or other agents used in this study (CLAG-M).

4. Diagnosis of acute promyelocytic leukemia, BCR/ABL1-positive AML or chronic myelogenous leukemia in blast crisis.

5. Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents.

6. Patients with a history of allo-SCT should not have active or acute chronic GVHD requiring systemic immunosuppression; topical GVHD treatment is allowed.

7. Participant has an uncontrolled infection. If a bacterial or viral infection is present, the participant must be receiving definitive therapy and has no signs of progressing infection for 72 hours prior to registration. If a fungal infection is present, the participant must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to registration.

   1. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection.
   2. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

8. Active hepatitis B virus (HBV) infection as evidenced by positive hepatitis B surface antigen and/or Nucleic Acid Amplification Testing (NAAT). Patients with prior history of cleared HBV infection (negative hepatitis B surface antigen, positive hepatitis B surface antibody, and positive hepatitis B core IgG antibody) could be allowed to participate after consultation with a hepatologist, in which case Hep B viral load will be monitored by qPCR per institutional guidelines. In this case, concomitant suppressive antiviral therapy against HBV might be warranted.

9. Uncontrolled HIV infection. Patients who have controlled infection on antiretroviral therapy are allowed, defined as HIV RNA below level of detection for the institution's standard assay.

10. History of heart failure, myocarditis, or cardiomyopathy which requires heart failure directed therapy.

11. Participant has long QT Syndrome at screening.

12. Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of triplicate determinations). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the Principal Investigator (PI).

13. Untreated CNS leukemia. Evaluation of cerebrospinal fluid (CSF) or brain MRI during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening. Patients who previously had CNS leukemia that resolved with therapy should undergo CSF sampling +/- brain MRI within 2 weeks prior to enrollment to exclude CNS relapse.

14. History of auto-immune conditions requiring active immunosuppressive therapy.

15. Patients with uncontrolled intercurrent illness including, but not limited to, symptomatic decompensated congestive heart failure; unstable angina pectoris; cardiac arrhythmia or any acute pulmonary condition requiring need for supplemental oxygen.

16. Participant is receiving concomitant drugs that are strong inducers of CYP3A except for drugs considered essential for the care of the patient.

17. Any medical condition which, in the investigator's opinion, could compromise the patient's safety.

18. Patients with psychiatric illness/social situations that would limit compliance with study requirements.

19. Pregnant or lactating women.

20. Participants who are receiving any other investigational treatment agents.