Vyxeos for Re-induction Treatment of Acute Myeloid Leukemia Patients with Persistent Disease After Induction

Inclusion Criteria:

• Subject or their legal guardian must be able to provide written informed consent

• Patients must have a diagnosis of acute myeloid leukemia

• Patients must have received standard continuous infusion cytarabine and daunorubicin (cytarabine 100-200 mg/m^2 by continuous infusion on days 1-7 and daunorubicin 45-90mg/m^2 on days 1-3) within the 14-33 days prior to starting trial treatment and havedocumented persistent disease (13-29 days from the start of 7+3 treatment). Patientswho have received a 7+3 regimen utilizing idarubicin (12 mg/m^2 on days 1-3) inplace of daunorubicin may enroll. Persistent disease will be defined as bone marrowcellularity of > 10-20% and bone marrow blast percentage of > 5-10% or clearevidence of immunophenotypically aberrant leukemia cells in the bone marrow. Thefinal determination of persistent AML will be made by the treating physician, butmust meet National Comprehensive Cancer Network (NCCN) criteria for persistentdisease. Enrollment of patients with less than 20% cellularity or less than 10%blasts will require approval of the principal investigator. Patients who receivedconcomitant treatment with another targeted therapy for AML (e.g. midostaurin)during initial induction may enroll, but will not continue to receive this treatmentduring Vyxeos treatment

• Patients must be deemed by the treating physician to be unlikely to achieve completeresponse (CR) without further therapy

• Patients must be deemed by the treating physician to be able to tolerate intensivechemotherapy (similar to 7+3 chemotherapy)

• Normal left ventricular ejection fraction (>= 50% by echocardiography or multi-gatedacquisition radionuclide angiocardiography [MUGA]) and lifetime daunorubicin dose ofless than 418 mg/m^2 (including recent course of 7+3)

• Eastern Cooperative Oncology Group (ECOG) functional status of 0, 1, or 2

• Aspartate aminotransferase (AST) < 5 x upper limit of normal (ULN) for the locallaboratory

• Alanine aminotransferase (ALT) < 5 x ULN for the local laboratory

• Total bilirubin < 1.5 x ULN (except for patients with known Gilbert?s syndrome) forthe local laboratory

• Calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40mL/min OR serum creatinine < 1.5 x the ULN for the local laboratory

• Female patients of childbearing potential must agree to use two forms ofcontraception from screening visit until 6 months following the last dose of studytreatment. Female patients must have a documented negative pregnancy test

• Male patients of childbearing potential having intercourse with females ofchildbearing potential must agree to abstain from heterosexual intercourse or havetheir partner use two forms of contraception from screening visit until 90 daysuntil the last dose of study treatment. They must also refrain from sperm donationfrom screening visit until 90 days following the last dose of study treatment

Exclusion Criteria:

• Acute promyelocytic leukemia (or M3 AML)

• Patients known to have core binding factor AML (defined as presence of t(8;21),inv(16), or other cytogenetically equivalent abnormalities)

• Patients known to have inactivating mutations of TP53 or evidence of an absence ofp53 protein activity as indicated by a monosomal karyotype. Monosomal karyotype willbe defined as two or more monosomies (loss of an entire chromosome or the entirelong arm of a chromosome [such as 7q-]) or a single monosomy in the setting of acomplex karyotype. Patients with a complex karyotype without a monosomy are eligibleto enroll

• Patients that the treating physician does not feel are able to tolerate intensivechemotherapy

• History of serious (>= grade 3) hypersensitivity reaction to cytarabine,daunorubicin, or any component of the formulation

• Known Wilson's disease or other symptomatic abnormality of copper metabolism (laboratory screening is not required in the absence of clinical or historicalevidence of Wilson's disease or other problems of copper metabolism)

• Total lifetime daunorubicin dose of more than 418 mg/m^2 (including recent course of 7+3) or equivalent total doses of other anthracycline medications

• Pregnancy or inability to use highly effective method of contraception for 6 monthsfollowing last dose of Vyxeos. Potentially fertile patients must have documentednegative serum pregnancy test. Breastfeeding should be avoided for at least 14 daysafter the last dose Vyxeos

• Patients with uncontrolled infection shall not be enrolled until infection istreated and brought under control. As infection is a common feature of AML, patientswith active infections are permitted to enroll provided that the infection is undercontrol

• Patients who have received an investigational agent (for any indication) within 5half-lives of the agent and until toxicity from this has resolved to grade 1 orless; if the half-life of the agent is unknown, patients must wait 4 weeks prior tofirst dose of study treatment. An investigational agent is one for which there is noapproved indication by the United States (US) Food and Drug Administration (FDA)

• Patients with psychological, familial, social, or geographic factors that otherwisepreclude them from giving informed consent, following the protocol, or potentiallyhamper compliance with study treatment and follow-up

• Any other significant medical condition, including psychiatric illness or laboratoryabnormality, that would preclude the patient participating in the trial or wouldconfound the interpretation of the results of the trial

• Patients with the following will be excluded: uncontrolled intercurrent illnessincluding, but not limited to, symptomatic congestive heart failure, unstable anginapectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior toenrollment, New York Heart Association (NYHA) class III or IV heart failure, severeuncontrolled ventricular arrhythmias, or electrocardiographic evidence of acuteischemia or active conduction system abnormalities

• Other malignancy currently requiring active therapy (except minor surgery fornon-melanoma skin cancer and for hormonal/anti-hormonal treatment, e.g. in prostateor breast cancer)