Houston, Texas 77030


Purpose:

Objectives: 1.1 Primary Objectives 1.1.1 To determine the overall response rate (ORR) including CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) + partial remission (PR) within 3 months of treatment initiation of quizartinib and decitabine combination in patients with newly diagnosed or relapsed FLT3-ITD mutated AML. 1.1.2 To determine the safety and Maximum Tolerable Dose (MTD) of this combination. 1.2 Secondary Objectives: 1.2.1 To determine CR and CR+CRh rates within 3 months of treatment initiation of quizartinib and decitabine combination in patients with newly diagnosed or relapsed FLT3-ITD mutated AML. 1.2.2 To determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), and number of patients bridged to hematopoetic stemcell transplant (HSCT) and median duration to HSCT from the initiation of the combination. 1.2.3 To investigate correlations of response to this combination with a pre-therapy, on-therapy, and progression 81-gene panel of gene mutations in AML and FLT3-ITD allele burden by RT-PCR. 1.2.4 To determine the effect of this combination therapy on in-vivo FLT3 inhibition


Criteria:

Inclusion Criteria: 1. Diagnosis of 1) AML (WHO classification definition of >/= 20% blasts) excluding acute promyelocytic leukemia (APL) or 2) MDS with > 10% blasts (defined by the IPSS classification). 2. For frontline Cohort: Patients aged >/= 60 years old who are not candidates for intensive in duction therapy and agree to receive the proposed combination therapy will be enrolled. 3. For relapsed cohort: Patients aged >/= 18 years old. (Patients who are candidates for relapse cohort will be enrolled into the study regardless of their fitness for intensive chemotherapy). 4. 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, 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. 5. For relapsed cohort: Patients who have received at least one prior therapy for AML or for MDS with > 10% blasts will be eligible. Patients may have received up to 3 prior regimens for AML and/or MDS (defined by the IPSS classification). Prior therapy for AML or MDS will be counted as a prior salvage. Patients who receive MDS directed therapies considered not purely supportive such as HMAs, lenalidomide, investigational therapies, will be enrolled to the salvage cohort if they are otherwise eligible. 6. 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. The half-life for the therapy in question will be based on published pharmacokinetic literature and will be documented in the protocol eligibility document. 7. 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 CNS leukemia at the discretion of the PI and with the agreement of the Sponsor. Controlled CNS leukemia is defined by the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the most recent 2 simultaneous CSF evaluations (2) Use of one dose 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. 8. Detection of FLT3-ITD mutation or FLT3-ITD/TKD co-mutations in bone marrow and/or peripheral blood samples within 30 days prior to study enrollment 9. ECOG performance status </=2 10. Serum biochemical values with the following limits unless considered due to leukemia, hemolysis or congenital disorder (Creatinine < 1.8 mg/dl, Total bilirubin < 1.8 mg/dL, (SGPT) <2.5x upper limit of normal) 11. Ability to take oral medication. 12. Ability to understand and provide signed informed consent. 13. Baseline left ventricular ejection fraction by ECHO or MUGA >/= 50%. 14. 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. 15. WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy until at least 3 months 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. 16. Negative urine or serum pregnancy test. Exclusion Criteria: 1. Patients with known allergy or hypersensitivity to quizartinib, mannitol, decitabine or any of their components. 2. Prior quizartinib use 3. Patients with known uncontrolled CNS leukemia 4. Only for frontline cohort: patients who are fit for intensive chemotherapy 5. Patients with electrolyte abnormalities at study entry defined as follows: Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L Serum magnesium above or below the institutional normal limit despite adequate management. Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management 6. Patients with known significant impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of quizartinib 7. 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 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. 8. Patients with a known HIV infection 9. 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 HBV [i.e., HBs Ag-, and anti-HBs+] may participate. 10. Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment. 11. Patients who have had any major surgical procedure within 14 days of Day 1. 12. Impaired cardiac function including any of the following: Screening ECG with a QTc>450 msec. The QTc interval will be calculated by Fridericia's correction factor (QTcF) at Screening and on Day 5 prior to the first dose of AC220. The QTcF will be derived from the average QTcF in triplicate. If QTcF>450 msec on Day 5, AC220 will not be given. 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. CHF NY Heart Association class III or IV. (continued below) 13. (cont) Atrial fibrillation documented within 2 weeks prior to first dose of study drug. Patients who are actively taking a strong CYP3A4 inducing medication [see appendix] 14. Patients who require treatment with concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors 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. 15. Known family history of congenital long QT syndrome.


NCT ID:

NCT03661307


Primary Contact:

Principal Investigator
Musa Yilmaz
M.D. Anderson Cancer Center

Musa Yilmaz
Phone: 713-745-9945
Email: myilmaz@mdanderson.org


Backup Contact:

N/A


Location Contact:

Houston, Texas 77030
United States

Musa Yilmaz
Phone: 713-745-9945

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: February 04, 2019

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