Phase 3 Study of Quizartinib with Chemotherapy in FLT3-ITD Negative Acute Myeloid Leukemia Patients
- Trial ID
- 2023-507936-20-00
- Protocol
- AC220-168
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the effect of **quizartinib** versus placebo, both administered in combination with standard induction and consolidation chemotherapy, and subsequently as maintenance therapy for up to 36 cycles, on the primary endpoint of overall survival (OS) in participants with newly diagnosed FLT3-ITD negative **acute myeloid leukemia** (AML). This objective is clinically relevant as it aims to determine the efficacy of quizartinib in improving survival outcomes in this patient population, which could potentially lead to advancements in treatment protocols for AML.
Secondary objectives include:
- Comparing event-free survival (EFS) between Arm A and Arm B.
- Assessing the duration of complete response (DoCR) between the two arms.
- Evaluating relapse-free survival (RFS) between Arm A and Arm B.
- Determining the complete remission rate (CR) between the two arms.
- Assessing CR with minimal or measurable residual disease (MRD) negativity.
- Further characterizing the safety profile of quizartinib when administered with standard chemotherapy and as maintenance therapy.
- Evaluating the pharmacokinetics (PK) of quizartinib and its metabolite (AC886).
Participants
The clinical trial involves a total of **433 participants** diagnosed with **acute myeloid leukemia** (AML). The study population includes both male and female subjects, aged between 18 and 70 years, who are newly diagnosed with morphologically documented primary AML based on the World Health Organization (WHO) 2016 classification. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial population was selected based on their eligibility to undergo standard "7+3" induction chemotherapy regimen, as assessed by the investigator. Participants must be competent to comprehend and sign an informed consent form and be willing to comply with scheduled visits and trial procedures. Both male and female participants are required to adhere to specific reproductive health guidelines, including the use of highly effective birth control methods during the trial and for a specified period after the last dose of the investigational drug. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring that ethical considerations are in place to protect these individuals throughout the study. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is a **Phase 3, double-blind, randomized, placebo-controlled** study designed to evaluate the efficacy of **quizartinib** in combination with induction and consolidation chemotherapy, followed by maintenance therapy, in adult patients with newly diagnosed **FLT3-ITD negative acute myeloid leukemia** (AML). The primary objective is to compare the overall survival (OS) between participants receiving quizartinib and those receiving a placebo. The trial is expected to commence recruitment on April 25, 2025, and conclude by September 28, 2029.
Participants will be randomly assigned to receive either quizartinib or a matching placebo, in addition to standard chemotherapy regimens. The trial will include several phases: induction, consolidation, and maintenance. The induction phase involves the administration of standard "7+3" chemotherapy, followed by the consolidation phase for those achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). The maintenance phase will commence within 60 days of the last consolidation cycle or within 180 days post-allogeneic hematopoietic stem cell transplantation (HSCT), provided the participant is stable.
The study will involve multiple visits, starting with a screening visit to assess eligibility based on inclusion criteria such as age, performance status, and laboratory results. Follow-up visits will occur throughout the trial to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.
Participant involvement is expected to last up to 36 cycles of maintenance therapy, with the total duration varying based on individual response and treatment phase transitions. Conditions that may lead to early termination from the study include failure to achieve CR or CRi, relapse, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring informed consent and compliance with all regulatory requirements.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Daunorubicin hydrochloride** is provided as "Daunoblastin 20 mg Pulver zur Herstellung einer Infusions- oder Injektionslösung," a **solution for injection/infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 60 mg/m² and a total dose not exceeding 360 mg/m² over a treatment period of up to 6 cycles. The product is manufactured by Pfizer Corporation Austria Ges.m.b.H.
**Quizartinib dihydrochloride** is administered in the form of a **film-coated tablet** under the product name "Quizartinib." The oral administration of this medication is conducted with a maximum daily dose of 60 mg and a total dose of up to 65,520 mg over a maximum treatment period of 1092 days. The product is developed by Daiichi Sankyo, Inc., and is identified by the sponsor product code AC220.
A **matching placebo** is also utilized in the study, provided as tablets without any active substance. These placebo tablets are designed to match the appearance of the Quizartinib tablets to maintain the double-blind nature of the trial.
**Cytarabine** is administered as "Citarabina Hikma 100mg/5mL Soluzione Iniettabile," a **solution for injection**. This medication is delivered via **intravenous infusion** with a maximum daily dose of 6000 mg/m² and a total dose not exceeding 74,800 mg/m² over a treatment period of up to 26 cycles. The product is supplied by Hikma Farmacêutica (Portugal), S.A.
**Idarubicin hydrochloride** is provided as "Idarubicin Ebewe 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung," a **solution for infusion**. It is administered through **intravenous infusion** with a maximum daily dose of 12 mg/m² and a total dose not exceeding 72 mg/m² over a treatment period of up to 6 cycles. The product is manufactured by EBEWE Pharma.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these treatments in adult patients with newly diagnosed FLT3-ITD negative Acute Myeloid Leukemia (AML).
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)** in participants with newly diagnosed FLT3-ITD negative Acute Myeloid Leukemia (AML). This primary endpoint will compare the effect of quizartinib versus placebo when administered with standard induction and consolidation chemotherapy, followed by maintenance therapy. Secondary endpoints include **Event-Free Survival (EFS)**, which accounts for failure to achieve complete remission (CR) at the end of induction, relapse after CR, or death from any cause. Additionally, the **Duration of Complete Response (DoCR)**, **Relapse-Free Survival (RFS)**, and the **Complete Remission Rate (CR)** will be evaluated. The trial will also assess CR with minimal or measurable residual disease (MRD) negativity, incidence of treatment-emergent adverse events (TEAEs), and pharmacokinetic parameters such as plasma concentrations and PK parameters (AUC24h, Cmax, Cmin, Tmax, and accumulation ratio).
Data collection will occur at various time points throughout the trial, including during the induction, consolidation, and maintenance phases. The trial will utilize local laboratory results to confirm CR or CRi at the end of the induction phase and to monitor MRD levels. Safety assessments will include changes in vital signs, ECG, safety laboratory evaluations, and physical examinations. The trial is designed to ensure rigorous and systematic evaluation of the efficacy of quizartinib in combination with chemotherapy in improving survival outcomes for patients with AML.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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)
- (ECOG) performance status (at the time the participant signs their ICF) of 0-2.
- Participant is a candidate for standard “7+3” induction chemotherapy regimen as specified in the protocol per investigator assessment.
- Required baseline local laboratory data (see details on page 165)
- 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)
- 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.
- 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.
- 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.
- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other trial procedures, and trial restrictions
- Consolidation Phase: Achieved CR or CRi, based on local laboratory results, at the end of the Induction Phase
- Consolidation Phase: Able to begin Consolidation Phase within 60 days of Day 1 of the last Induction cycle
- 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
- 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
- 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).
- 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.
- Maintenance Phase: For participants who undergo allo-HSCT: Participant has not initiated therapy for active GVHD (prophylaxis is allowed) within 21 days
- 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).
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) (see details on pg 167)
- Diagnosis of AML secondary to prior chemotherapy or radiotherapy
- 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.
- 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 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;
- 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 (for details see page 168)
- 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 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.
- 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.
- 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 including where other treatment options, such as gemtuzumab ozogamicin, are preferred according to local institutional practice.
- Treatment with any strong or moderate CYP3A inducers within 2 weeks or 5 half-lives of randomization whichever is longer.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 Apr 2025 | 10 |
 Belgium | Not Recruiting | 25 Apr 2025 | 12 |
 Bulgaria | Not Recruiting | 25 Apr 2025 | 25 |
 Croatia | Not Recruiting | 25 Apr 2025 | 12 |
 Czechia | Not Recruiting | 25 Apr 2025 | 13 |
 France | Not Recruiting | 25 Apr 2025 | 25 |
 Germany | Not Recruiting | 25 Apr 2025 | 19 |
 Hungary | Not Recruiting | 25 Apr 2025 | 12 |
 Italy | Not Recruiting | 25 Apr 2025 | 37 |
 Norway | Not Recruiting | 25 Apr 2025 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Quizartinib | Test | FILM-COATED TABLET | ORAL USE | 60 | 1092 | PRD11781566 |
Citarabina Hikma 100mg/5mL Soluzione Iniettabile | Other | SOLUZIONE INIETTABILE | INTRAVENOUS INFUSION | 6000 | 26 | PRD5259318 |
Daunoblastin 20 mg Pulver zur Herstellung einer Infusions- oder Injektionslösung | Other | PULVER ZUR HERSTELLUNG EINER INFUSIONS- ODER INJEKTIONSLÖSUNG | INTRAVENOUS INFUSION | 60 | 6 | PRD11825203 |
Matching placebo tablets without active substance | Placebo | N/A | — | — | — | N/A |
Idarubicin Ebewe 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | 12 | 6 | PRD11937586 |
Quizartinib | Test | FILM-COATED TABLET | ORAL USE | 60 | 1092 | PRD11781567 |