Liposomal Cytarabine and Daunorubicin (CPX-351) and Quizartinib for the Treatment of Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

Inclusion Criteria

• Diagnosis of 1) AML (World Health Organization [WHO] classification definition of >= 20% blasts, excluding all core binding factor AML patients and acute promyelocytic leukemia ([APL] patients, or 2) High and very high risk score MDS per Revised International Prognostic Scoring System (IPSS-R) criteria
• For frontline cohort: Patients aged >= 60 years old
• For relapsed or refractory cohort: Patients aged >= 18 years old
• For frontline cohort: Patients must be chemonaive, i.e., not have received any chemotherapy (except hydrea or 1-2 doses of ara-C for transient control of hyperleukocytosis) for AML or MDS. They may have received transfusions, hematopoietic growth factors or vitamins for an antecedent hematological disorder (AHD) or for AML. Temporary prior measures such as apheresis, ATRA (all-trans retinoic acid), steroids or hydrea while diagnostic work-up is being performed are allowed and not counted as a prior salvage. Supportive care therapy for MDS (growth factors, transfusions) will not be considered as prior therapy for MDS/AML and these patients will be enrolled to the frontline cohort of the study if they are otherwise eligible
• For relapsed or refractory cohort: Patients who have received at least one prior therapy for AML or for MDS blasts will be eligible. Patients may have received up to 4 salvage regimens for AML and/or MDS (defined by the International Prognostic Scoring System [IPSS] classification). Patients who receive MDS directed therapies considered not purely supportive such as hypomethylating agents (HMAs), lenalidomide, investigational therapies, will be enrolled to the salvage cohort if they are otherwise eligible
• In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of protocol therapy will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for cytotoxic/noncytotoxic agents (whichever is shorter). The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure’s, or drug-administration manuals) and will be documented in the protocol eligibility document. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intrathecal (IT) therapy for patients with controlled central nervous system (CNS) leukemia at the discretion of the principal investigator (PI). (2) Use of cytarabine (up to 2 g/m^2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. These medications will be recorded in the case-report form
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Serum biochemical values with the following limits unless considered due to leukemia
• Creatinine < 1.8 mg/dl
• Total bilirubin < 1.8 mg/dL, unless increase is due to hemolysis or congenital disorder
• Transaminases (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN)
• Potassium, magnesium, and calcium (normalized for albumin) levels should be within institutional normal limits
• Ability to take oral medication
• Ability to understand and provide signed informed consent
• Baseline left ventricular ejection fraction by echocardiogram (ECHO) or multigated acquisition scan (MUGA) >= 50%
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential
• WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy until at 30 days after the last dose of investigational drug. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) as well as men with azoospermia do not require contraception. Appropriate methods of birth control include: birth control pills, condoms, intrauterine device (IUD), or other Food and Drug Administration (FDA) approved birth control methods
• Patients may be concurrently enrolling in supportive care clinical trials. Other investigational agents that are used for treatment of other cancers will not be allowed
• Patients in the relapsed/refractory cohort who have met their lifetime cap (450 mg/m^2 daunorubicin or its equivalent) and who would exceed this cap after planned protocol are not eligible

Exclusion Criteria

• Patients with known allergy or hypersensitivity to quizartinib, mannitol, CPX-351 or any of their components
• Patients with electrolyte abnormalities at study entry defined as follows: * Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L * Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management * Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management
• Patients with known significant impairment of gastrointestinal (GI) function or GI disease as determined by the investigator that may significantly alter the absorption of quizartinib
• Patients with any other known concurrent severe and/or uncontrolled medical condition including but not limited to diabetes, cardiovascular disease including hypertension, renal disease, or active uncontrolled infection, which as determined by the investigator could compromise participation in the study. Patients on active antineoplastic or radiation therapy for a concurrent malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed
• Patients with a known human immunodeficiency virus (HIV) infection (HIV testing is not required prior to enrollment)
• Patients with known positive hepatitis B or C infection by serology, with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required prior to study entry). Subjects with serologic evidence of prior vaccination to hepatitis B virus (HBV) (i.e., hepatitis surface antigen [HBs Ag]-, and anti-HBs+) may participate
• Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) within 3 days prior to the initiation of study treatment
• Patients who have had any major surgical procedure within 14 days of day 1
• Impaired cardiac function including any of the following: * Screening electrocardiogram (ECG) with a Fridericia’s correction factor (QTcF) > 450 msec. The QTcF interval will be calculated by Fridericia’s correction factor (QTcF). The QTcF will be derived from the average QTcF in triplicate. Patients are excluded if they have QTcF >/= 450. Subjects with prolonged QTcF interval in the setting of bundle branch blocks may participate if QTcR < 450 upon review and approval by the Principal Investigator (PI) or Co-Principal Investigator (co-PI). In patients with branch bundle blocks, electrocardiogram (EKGs) may not reflect QTc duration properly. Therefore, the Cardiology collaborator for this study will manually review to provide an accurate reading of the QTc. In the case when the cardiology collaborator is not readily available to review the result, PI or co-PI will calculate QTcR using an online calculating tool
• Patients with congenital long QT syndrome
• History or presence of sustained ventricular tachycardia requiring medical intervention
• Any history of clinically significant ventricular fibrillation or torsades de pointes
• Known history of second or third degree heart block (may be eligible if the patient currently has a pacemaker)
• Sustained heart rate of < 50/minute on pre-entry ECG
• Right bundle branch block + left anterior hemiblock (bifascicular block)
• Complete left bundle branch block
• Patients with myocardial infarction or unstable angina within 6 months prior to starting study drug
• Congestive heart failure (CHF) New York (NY) Heart Association class III or IV
• Poorly rate controlled atrial fibrillation or atrial fibrillation with clinical symptoms documented within 2 weeks prior to first dose of study drug
• Patients who are actively taking a strong CYP3A4 inducing medication (regardless of quizartinib dose level)
• Patients who are actively taking a strong CYP3A4 inhibitor (only for dose level 0). Strong CYP3A4 inhibitors will be allowed for patients treated on dose level 1
• Patients who require treatment with concomitant drugs that prolong QT/QTc interval with the exception of antibiotics, antifungals, and antivirals that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject or if the Investigator believes that beginning therapy with a potentially QTc-prolonging medication (such as anti-emetic) is vital to an individual subject’s care while on study
• Known family history of congenital long QT syndrome
• Total lifetime anthracycline exposure exceeding the equivalent of 368 mg/m^2 of daunorubicin (or equivalent) prior to start of study therapy * It is recommended that all patients treated with CPX-351 limit the lifetime exposure to anthracyclines to not more than 500mg/m2, including the daunorubicin received via CPX-351 during first induction. (Prior anthracycline exposure 368 mg/m2 plus anthracycline exposure from CPX-351 in a single induction course 132 mg/m^2 = 500 mg/m^2) Thereafter, subsequent induction and consolidation courses will be given based on perceived potential benefit:risk considerations even if the total anthracycline exposure exceeds 500 mg/m^2