QUIZARTINIB DIHYDROCHLORIDE for Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- 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\n- Male participants must not freeze or donate sperm starting at screening and throughout the trial period, and at least 4 months after the last dose of quizartinib/placebo, or for 6 months following the last dose of cytotoxic chemotherapy, whichever is later.\n- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other trial procedures, and trial restrictions\n- Consolidation Phase: Achieved CR or CRi, based on local laboratory results, at the end of the Induction Phase\n- Consolidation Phase: Able to begin Consolidation Phase within 60 days of Day 1 of the last Induction cycle\n- 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\n- Maintenance Phase: 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\n- Maintenance Phase: Able to begin Maintenance Phase within 60 days of Day 1 of the last Consolidation cycle received or within 180 days after allo-HSCT (ie, stable after transplant).\n- Maintenance Phase: For participants who undergo allo-HSCT: Participant does not have active acute or ≥Grade 3 graft-versus-host disease (GVHD)or severe chronic GVHD.\n- Maintenance Phase: For participants who undergo allo-HSCT: Participant has not initiated therapy for active GVHD (prophylaxis is allowed) within 21 days\n- Maintenance Phase: For participants who undergo allo-HSCT: All Grade 3 and 4 non-hematological toxicities have resolved to ≤Grade 2 (with the exception of alopecia).\n- ≥18 years or the minimum legal adult age (whichever is greater) and 70 years (at Screening)\n- Newly diagnosed, morphologically documented primary AML based on the World Health Organization (WHO) 2016 classification (at Screening)\n- (ECOG) performance status (at the time the participant signs their ICF) of 0-2.\n- Participant is a candidate for standard “7+3” induction chemotherapy regimen as specified in the protocol per investigator assessment.\n- Required baseline local laboratory data (see details on page 165)\n- 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 quizartinib/placebo or cytotoxic chemotherapy (i.e. anthracycline, cytarabine) whichever is later (see details on page 166)\n- Female participants must not donate, or retrieve for their own use, ova from the time of initiation of 7+3 chemotherapy and throughout the trial treatment period and for at least 7 months after the final trial drug administration.\n- If male, must be surgically sterile or willing to use highly effective birth control as well as a condom upon enrollment, during the treatment period, and for 4 months following the last dose of quizartinib/placebo, or for 6 months following the last dose of cytotoxic chemotherapy, whichever is later."}

Exclusion criteria

• {"criterion_text":"- 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) (see details on pg 167)\n- 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.\n- Uncontrolled or significant cardiovascular disease (for details see page 168)\n- 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.\n- 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 hepatitis B surface antigen positive (HBsAg+), with hepatitis B virus (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.\n- Has active primary immunodeficiency or active human immunodeficiency virus ( 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.\n- Uncontrolled hypothyroidism\n- History of severe hypersensitivity to any excipients in the quizartinib/placebo tablets\n- Females who are pregnant or breastfeeding\n- Otherwise considered inappropriate for the trial by the investigator including where other treatment options, such as gemtuzumab ozogamicin, are preferred according to local institutional practice.\n- Treatment with any strong or moderate CYP3A inducers within 2 weeks or 5 half-lives of randomization whichever is longer.\n- Diagnosis of AML secondary to prior chemotherapy or radiotherapy\n- Diagnosis of AML with known antecedent myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and others.\n- 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.\n- Prior treatment for AML, except for the following allowances prior to Day 1 of induction chemotherapy : a. Leukapheresis; b. Treatment for hyperleukocytosis with hydroxyurea; c. Cranial radiotherapy for central nervous system (CNS) leukostasis; d. Prophylactic intrathecal chemotherapy;\n- Prior treatment with quizartinib or other FLT3 inhibitors (eg, midostaurin, sorafenib).\n- 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.\n- Inadequate washout period before randomization, defined as major surgery <4 weeks or ≤2 weeks for low-invasive cases (eg, colostomy).\n- 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"}

Primary endpoints

• {"endpoint_text":"- Overall survival (OS) in participants with newly diagnosed FLT3 ITD negative AML","definition_or_measurement_approach":"Time from randomization to date of death due to any cause (overall survival, OS)"}

Secondary endpoints

• {"endpoint_text":"- (Arm A vs Arm B) Event-free survival (EFS): Time from randomization to date of failure to achieve CR (as assessed by IRC) at end of induction, relapse after CR, or death due to any cause, whichever occurs first","definition_or_measurement_approach":"Time from randomization to failure to achieve CR at end of induction (as per IRC), relapse after CR, or death, whichever occurs first"}
• {"endpoint_text":"- (Arm A vs Arm B) Duration of complete response (DoCR): Time from the first documented CR until documented relapse or death due to any cause, whichever comes first","definition_or_measurement_approach":"Time from first documented CR until documented relapse or death"}
• {"endpoint_text":"- (Arm A vs Arm B) Relapse Free Survival (RFS): Time from randomization, for participants who achieve CR in the Induction Phase, until relapse or death due to any cause, whichever comes first","definition_or_measurement_approach":"For participants achieving CR in Induction Phase: time from randomization until relapse or death"}
• {"endpoint_text":"- (Arm A vs Arm B) Complete remission rate (CR): Percentage of participants who achieved a CR","definition_or_measurement_approach":"Proportion of participants achieving complete remission (CR) as defined in protocol"}
• {"endpoint_text":"- (Arm A vs Arm B) CR with minimal or measurable residual disease (MRD) negativity: MRD negativity by NPM1, CBF, and FLT3-ITD (assessed individually in patients with NPM1 and CBF mutations present at screening and in all patients for FLT3-ITD MRD levels)","definition_or_measurement_approach":"MRD negativity assessed by NPM1, CBF and FLT3-ITD assays per protocol; assessed individually where mutations present at screening"}
• {"endpoint_text":"- (Arm A vs B) Incidence of treatment-emergent adverse events (TEAEs), serious (TEAEs), AESIs, changes in vital signs, ECG, safety laboratory evaluations and physical examinations","definition_or_measurement_approach":"Standard safety assessments: incidence and severity of TEAEs, serious TEAEs, adverse events of special interest, changes in vitals, ECG, labs and physical exams"}
• {"endpoint_text":"- (Arm A vs Arm B) Plasma concentrations at each time point and PK parameters (AUC24h, Cmax, Cmin, Tmax, and accumulation ratio and parent/metabolite ratio)","definition_or_measurement_approach":"Pharmacokinetic sampling to derive AUC24h, Cmax, Cmin, Tmax, accumulation ratio and parent/metabolite ratios"}
• {"endpoint_text":"- (Arm B vs C) OS: Time from randomization to date of death due to any cause","definition_or_measurement_approach":"Time from randomization to date of death due to any cause"}

Methods

• HCP outreach: provision of HCP Fact Sheets and HCP Letters to clinicians to support patient identification and referral (documents present for multiple countries)
• Printed and digital patient-facing materials: Patient Brochures, Patient Flyers and Welcome Booklets in local languages to inform patients and caregivers about the trial (country-specific materials available e.g., BE, ES, PL, PT, IT, FR and others)
• Caregiver engagement: Caregiver Brochures for family/caregivers to support recruitment and information sharing
• Referral/physician letters and inclusion-exclusion cards to facilitate clinician referrals (documents listed for several member states)
• Participant materials: Participant ID cards, dosing cards and pill diaries provided to participants as trial materials
• Patient-facing video: Patient Facing Video Transcript document available (used for participant information)

Primary sponsor

Full Name

Daiichi Sankyo Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Inotiv Inc.

Responsibilities

Bioanalysis/PK(QCP)

Name

IQVIA Limited

Responsibilities

Clinical trial services (codes: 1,12,13,2,4,5 as listed in submission)

Name

Suvoda LLC

Responsibilities

eClinical / data capture (code: 3)

Name

Labcorp Central Laboratory Services SARL

Responsibilities

Bioanalysis/PIA(QCP) PK Data Analysis

Name

Navigate Biopharma Services Inc.

Responsibilities

IVD manufacturer and documentation

Name

Eresearchtechnology Inc.

Responsibilities

eCOA

Name

Fortrea Inc.

Responsibilities

Operational support (code: 6)

Name

Almac Clinical Services LLC

Responsibilities

Central laboratory/clinical services (code: 14)

Third parties

• {"country":"United States","full_name":"Inotiv Inc.","duties_or_roles":"Bioanalysis/PK(QCP)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Codes: 1,12,13,2,4,5 (responsibilities per submission: multiple clinical trial support services)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"Code: 3 (electronic data capture / eClinical services)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Bioanalysis/PIA(QCP) PK Data Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Navigate Biopharma Services Inc.","duties_or_roles":"IVD Manufacturer, Providing IVD documents","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"eCoA","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"Code: 6 (clinic/operational support)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Almac Clinical Services LLC","duties_or_roles":"Code: 14 (laboratory/central services)","organisation_type":"Pharmaceutical company"}