IRB Study Number 25-017
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To compare the effect of quizartinib versus placebo (administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 36 cycles) on the primary endpoint of overall survival (OS) in participants with newly diagnosed FLT3-ITD negative AML
Secondary Objectives
Event-free survival (EFS)
Duration of complete response (DoCR)
Relapse-free survival (RFS)
Complete remission rate (CR)
CR with minimal or measurable residual disease (MRD) negativity
Further characterize the safety profile of quizartinib administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 36 cycles
Assess the pharmacokinetics (PK) of quizartinib and its metabolite (AC886)
Inclusion Criteria
5.1.1. Inclusion Criteria – Randomization
Must be competent and able to comprehend, sign, and date an Ethics Committee (EC)-or Institutional Review Board (IRB)-approved Informed Consent Form (ICF) before performance of any trial-specific procedures or tests.
≥18 years or the minimum legal adult age (whichever is greater) and 70 years (at Screening).
Newly diagnosed, morphologically documented primary AML based on the World Health Organization (WHO) 2016 classification (at Screening).54
Eastern Cooperative Oncology Group (ECOG) performance status (see Section 10.3.4 for descriptions) (at the time the participant signs their ICF) of 0-2.
Participant is receiving standard “7+3” induction chemotherapy regimen as specified in the protocol (Section 6.3.1 for required anthracycline and cytarabine doses).
Required baseline local laboratory data (within 7 days prior to start of trial drug administration):
a. Creatinine clearance >50 mL/min, as calculated with the modified Cockcroft-Gault equation (Section 10.3.1);
b. Total serum bilirubin (TBL) ≤1.5 × upper limit of normal (ULN) unless the participant has documented Gilbert’s syndrome or the increase is related to increased unconjugated (indirect) bilirubin due to hemolysis; For participants with Gilbert’s syndrome or hemolysis, direct bilirubin ≤1.5 x ULN;
c. Serum alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN;
d. Serum electrolytes within the institution’s normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia [Section 10.3.2], or ionized calcium) and magnesium. If outside of the institution’s normal range, participant will be eligible when electrolytes are corrected;
e. Adequate blood clotting function: International normalized ratio (INR)/prothrombin time (PT) and either activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) ≤1.5 × upper limit of normal (ULN) unless participant is receiving anticoagulant therapy in which case PT/INR or aPTT must be within therapeutic range of intended use of anticoagulants.
If a woman of childbearing potential, must have a negative serum pregnancy test upon entry into this trial and must be willing to use highly effective birth control upon enrollment, during the treatment period and for 7 months following the last dose of investigational drug. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). Acceptable methods of contraception are noted in Section 10.3.7.
Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the trial treatment period, and for at least 7 months after the final trial drug administration.
If male, must be surgically sterile or willing to use highly effective birth control upon enrollment, during the treatment period, and for 4 months following the last dose of investigational drug.
Male participants must not freeze or donate sperm starting at screening and throughout the trial period, and at least 4 months after the final trial drug administration.
Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other trial procedures, and trial restrictions.
5.1.2. Inclusion Criteria – Consolidation Phase
Achieved CR or CRi (as defined in Section 8.3.4), based on local laboratory results, at the end of the Induction Phase.
Able to begin Consolidation Phase within 60 days of Day 1 of the last Induction cycle.
5.1.3. Inclusion Criteria – Maintenance Phase
Confirmed <5% of blasts based on the most recent bone marrow aspirate, based on the local laboratory results, performed within 28 days prior to Cycle 1 Day 1 of maintenance therapy.
Absolute neutrophil count (ANC) >500/mm3 and platelet count >50,000/mm3 without platelet transfusion support within 24 hours prior to Cycle 1 Day 1 of maintenance therapy.
Able to begin Maintenance Phase within 60 days of Day 1 of the last Consolidation cycle received or within 180 days after allogeneic HSCT (ie, stable after transplant).
For participants who undergo allo-HSCT:
Participant does not have active acute or ≥Grade 3 GVHD.
Participant has not initiated therapy for active GVHD (prophylaxis is allowed) within 21 days.
All Grade 3 and 4 non-hematological toxicities have resolved to ≤Grade 2 (with the exception of alopecia).
Exclusion Criteria
Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); participants who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).
Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms or autoimmune/rheumatologic conditions.
Diagnosis of AML secondary to myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including CMML, aCML, JMML and others.
Participants with newly diagnosed AML with FLT3-ITD mutations (FLT3-ITD [+]) present at ≥5% VAF (or ≥0.05 SR) based on a validated FLT3 mutation assay.
Prior treatment for AML, except for the following allowances:
a. Leukapheresis;
b. Treatment for hyperleukocytosis with hydroxyurea;
c. Cranial radiotherapy for central nervous system (CNS) leukostasis;
d. Prophylactic intrathecal chemotherapy;
e. Growth factor/cytokine support.
Prior treatment with quizartinib or other FLT3 inhibitors (eg, midostaurin, sorafenib).
Prior treatment with any investigational drug or device within 30 days prior to randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures.
Inadequate washout period before randomization, defined as major surgery <4 weeks or ≤2 weeks for low-invasive cases (eg, colostomy).
Known CNS leukemia, including cerebrospinal fluid positive for AML blasts; lumbar puncture is recommended for participants with symptoms of CNS leukemia to rule out extramedullary CNS involvement.
History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated with no evidence of disease for at least 2 years.
Uncontrolled or significant cardiovascular disease, including any of the following: a. Bradycardia of less than 50 beats per minute, unless the participant has a pacemaker;
b. QTcF interval >450 ms;
c. Diagnosis of or suspicion of congenital long QT syndrome (including family history of congenital long QT syndrome);
d. Severe and uncontrolled hypertension, defined as systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg, despite optimal medical management;
e. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
f. History of second- (Mobitz II) or third-degree heart block (participants with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker);
g. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
h. History of New York Heart Association Class 3 or 4 heart failure (see Section 10.3.3 for descriptions);
i. Left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal per multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) done within 30 days prior to randomization;
j. Complete left bundle branch block;
k. Severe aortic stenosis.
Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy. Note: Participants with localized fungal infections of skin or nails are eligible.
Known active clinically relevant liver disease (eg, active hepatitis B or active hepatitis C), based on available blood tests, liver ultrasound, or liver biopsy results. Participants who are HBsAg+, with HBV infection for more than 6 months, have an HBV DNA viral load <2000 IU/mL, have normal transaminase values at baseline, and are willing to start and maintain antiviral treatment for the duration of the trial are allowed.
Has active primary immunodeficiency or active HIV infection as determined by plasma HIV RNA viral load and CD4 count. Participants with undetectable viral load or normalized CD4 count (CD4+ T-cell counts ≥350 cells/μL) and no opportunistic infection within the past 12 months will be eligible. These participants must be on established antiretroviral therapy for at least 4 weeks and have an HIV viral load <400 copies/mL prior to enrollment. Participants should be tested for HIV prior to randomization if required by local regulations or EC.
Uncontrolled hypothyroidism.
History of severe hypersensitivity to any excipients in the quizartinib/placebo tablets.
Females who are pregnant or breastfeeding.
Otherwise considered inappropriate for the trial by the investigator.
