Trial to Compare Efficacy and Safety of Chemotherapy/Quizartinib vs Chemotherapy/Placebo in Adults FMS-like Tyrosine Kinase 3 (FLT3) Wild-type Acute Myeloid Leukemia (AML)

A 2:1 Randomized Phase II Trial to Compare the Efficacy and Safety of Standard Chemotherapy Plus Quizartinib Versus Standard Chemotherapy Plus Placebo in Adult Patients With Newly Diagnosed FLT3 Wild-type AML

Randomized phase II trial to compare the efficacy and safety of standard chemotherapy plus quizartinib versus standard chemotherapy plus placebo in adult patients with newly diagnosed FLT3 wild-type Acute Myeloid Leukemia

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Quizartinib; Drug: Cytarabine; Drug: Idarubicin; Drug: Placebo oral tablet

Detailed Description

Multicenter, prospective, randomized, placebo-controlled, double-blinded phase II trial to assess the efficacy and safety of an oral quizartinib vs. placebo containing front-line chemotherapy-based schedule in FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) wild-type Acute Myeloid Leukemia patients.

The trial will be conducted in two phases:

An open-label safety run-in phase: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Quizartinib 60 mg/d x 14 days (30mg with strong Cytochrome P450 Family 3 Subfamily A (CYP3A) inhibitor) in a total of 9 patients, being observed during 1 cycle of induction to define the final dose for the randomized phase.

A randomized double-blinded phase 2:1 quizartinib (at the established dose) vs. placebo.

Experimental Arm: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Quizartinib 60 mg/d x 14 days (30mg with strong CYP3A inhibitor) Standard Arm: Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3) Placebo 60 mg/d x 14 days (30mg with strong CYP3A inhibitor)

272 patients will be included in this phase.

• Study Type: Interventional
• Enrollment (Actual): 273
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Albacete, Spain, 02006
    • Complejo Hospitalario de Albacete
  • Alicante, Spain, 03010
    • Hospital General Universitario de Alicante
  • Almería, Spain, 04004
    • Complejo Hospitalario Torrecárdenas
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall Hebrón
  • Burgos, Spain, 09006
    • Hospital Universitario De Burgos
  • Cadiz, Spain
    • Hospital Puerta del Mar
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcántara
  • Córdoba, Spain, 14004
    • Complejo Hospitalario Regional Reina Sofía
  • Huelva, Spain, 21005
    • Hospital Juan Ramón Jimenez
  • Jaén, Spain, 23007
    • Complejo Hospitalario de Jaén
  • Lugo, Spain, 27003
    • Complejo Hospitalario Lucus Augusti
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28040
    • Fundación Jiménez Díaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital La Paz
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Murcia, Spain
    • Hospital Virgen de la Arrixaca
  • Málaga, Spain, 29010
    • Hospital Regional Universitario Malaga
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Oviedo, Spain, 33006
    • Hospital Universitario Central de Asturias
  • Pamplona, Spain, 31008
    • Complejo Universitario de Navarra
  • Pontevedra, Spain, 36071
    • Complejo Hospitalario de Pontevedra
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Sevilla, Spain, 41013
    • Complejo Hospitalario regional Virgen del Rocio
  • Talavera De La Reina, Spain
    • Hospital Nuestra Señora del Prado
  • Toledo, Spain, 45004
    • Complejo Hospitalario de Toledo
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
  • Valencia, Spain, 46017
    • Hospital Universitario Dr. Peset Aleixandre
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario Valencia
  • Valladolid, Spain, 47003
    • Hospital Clínico Universitario de Valladolid
  • Zaragoza, Spain, 50009
    • Hospital Clinico Universitario Lozano Blesa
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • A Coruña
    • Santiago De Compostela, A Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago
    • Santiago De Compostela, A Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de A Coruña
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
  • Castellón
    • Castellón De La Plana, Castellón, Spain, 12004
      • Hospital General Univesitario de Castellón
  • Las Palmas
    • Las Palmas De Gran Canaria, Las Palmas, Spain, 35020
      • Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
  • Madrid
    • Pozuelo De Alarcón, Madrid, Spain, 28223
      • Hospital Universitario Quiron Salud Madrid
  • Murcia
    • Cartagena, Murcia, Spain, 30200
      • Hospital General Universitario Santa Lucia
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36312
      • Complejo Hospitalario Universitario de Vigo
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Hospital Universitario de Canarias
  • Vizcaya
    • Bilbao, Vizcaya, Spain, 48013
      • Hospital Universitario de Basurto
    • Galdakao, Vizcaya, Spain, 48960
      • Hospital Universitario de Galdakao
  • Álava
    • Vitoria, Álava, Spain, 01009
      • Hospital Txagorritxu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent before the first screening procedure. The patient and the investigator must sign informed consent form.
2. Diagnosis of untreated AML (according to the World Health Organization (WHO) 2008/2016 definition)
3. Age ≥ 18 and ≤70 years old at the time of screening
4. Non-FLT3-ITD (allelic ratio <0.03) at diagnosis
5. Considered eligible to receive intensive chemotherapy as per investigator judgment
6. Eastern Cooperative Oncology Group (ECOG) 0-2
7. No contraindications for quizartinib
8. The subject is receiving standard "7+3" induction chemotherapy regimen as specified in the protocol
9. No severe organ function abnormalities
10. Not included in other first-line trials
11. Cardiac ejection fraction ≥ 45% assessed by echocardiography or multiple-gated acquisition (MUGA).
12. Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception upon enrollment, during the treatment period and for 3 months following the last dose of investigational drug or cytarabine, whichever is later
13. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential) upon enrollment, during the treatment period, and for 3 months following the last dose of investigational drug or cytarabine, whichever is later
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Patients with a genetic diagnosis of acute promyelocytic leukemia
2. Age <18 years or >70 years
3. ECOG performance status of 3 or 4

4. Prior treatment for AML, except for the following allowances:

   c) Leukapheresis d) Treatment for hyperleukocytosis with hydroxyurea

5. Blastic phase of bcr/abl chronic myeloid leukemia.

6. Presence of an associated active and/or uncontrolled malignancy:

   - Patients with another neoplastic disease, for whom the Investigator has a clinical suspicion of active disease at the time of enrollment. Note: Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study. Hormonal or adjuvant therapies will be allowed for breast cancer or prostate cancer as long as they are on a stable dose for at least 2 weeks before the first dose.

7. Known active and not controlled hepatitis B or hepatitis C infection. In the event of a positive viral load, please consult with the Sponsor
8. Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)
9. Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial
10. Serum creatinine ≥ 250 μmol/l (≥ 2.5 mg/dL) (unless it is attributable to AML activity)
11. Bilirubin, alkaline phosphatase, or Serum glutamic oxaloacetic transaminase (SGOT) > 3 times the normal upper limit (unless it is attributable to AML activity)

12. Uncontrolled or significant cardiovascular disease, including any of the following:

    1. Symptomatic bradycardia of fewer than 50 beats per minute, unless the subject has a pacemaker;
    2. QT Comparison of Fridericia's (QTcF) >450 msec at Screening. Note: QTcF will be derived from the mean of triplicate readings;
    3. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
    4. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥ 110 mmHg;
    5. History of clinically relevant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes)
    6. History of a second (Mobitz II) or third-degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker)
    7. An ejection fraction <45%
    8. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening
    9. History of New York Heart Association Class 3 or 4 heart failure
    10. Right bundle branch and left anterior hemiblock (bifascicular block), complete left bundle branch block
13. History of hypersensitivity to any excipients in the quizartinib/placebo tablets
14. Females who are pregnant or breastfeeding
15. Any patients with known significant impairment in gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of quizartinib.
16. Active acute or chronic Graft-Versus-Host-Disease (GVHD) requiring prednisone >10 mg or equivalent corticosteroid daily.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Quizartinib; Induction: Cytarabine continuous IV infusion 200 mg/m2 (days 1-7), Idarubicin IV infusion 12 mg/m2 (days 1-3), oral quizartinib (dose defined in safety run-in phase) 14 days (8-21) (dose will be halved with strong CYP3A inhibitor), up to 2 cycles of 35 days. Consolidation: Cytarabine IV infusion 1,5-3 g/m2 (days 1, 3, 5), oral quizartinib (dose defined in safety run-in phase) 14 days (6-19) (dose will be halved with strong CYP3A inhibitor), up to 4 cycles of 35 days. Maintenance: oral quizartinib 60mg/day (dose will be halved with strong CYP3A inhibitor), up to 12 cycles of 28 days	Drug: Quizartinib; Induction: oral quizartinib (dose defined in safety run-in phase) 14 days (8-21) (dose will be halved with strong CYP3A inhibitor), up to 2 cycles of 35 days. Consolidation: oral quizartinib (dose defined in safety run-in phase) 14 days (6-19) (dose will be halved with strong CYP3A inhibitor), up to 4 cycles of 35 days. Maintenance: oral quizartinib 60mg/day (dose will be halved with strong CYP3A inhibitor), up to 12 cycles of 28 days.; Drug: Cytarabine; Induction: Cytarabine continuous IV infusion, 200 mg/m2 (days 1-7), up to 2 cycles of 35 days. Consolidation: Cytarabine IV infusion, 1,5-3 g/m2 (days 1, 3, 5), up to 4 cycles of 35 days.; Drug: Idarubicin; Induction: Idarubicin IV infusion 12 mg/m2 (days 1-3), up to 2 cycles of 35 days.
Placebo Comparator: Placebo; Induction: Cytarabine continuous IV infusion 200 mg/m2 (days 1-7), Idarubicin IV infusion 12 mg/m2 (days 1-3), oral placebo (dose defined in safety run-in phase) 14 days (8-21) (dose will be halved with strong CYP3A inhibitor), up to 2 cycles of 35 days. Consolidation: Cytarabine IV infusion 1,5-3 g/m2 (days 1, 3, 5), oral placebo (dose defined in safety run-in phase) 14 days (6-19) (dose will be halved with strong CYP3A inhibitor), up to 4 cycles of 35 days. Maintenance: oral placebo 60mg/day (dose will be halved with strong CYP3A inhibitor), up to 12 cycles of 28 days.	Drug: Cytarabine; Induction: Cytarabine continuous IV infusion, 200 mg/m2 (days 1-7), up to 2 cycles of 35 days. Consolidation: Cytarabine IV infusion, 1,5-3 g/m2 (days 1, 3, 5), up to 4 cycles of 35 days.; Drug: Idarubicin; Induction: Idarubicin IV infusion 12 mg/m2 (days 1-3), up to 2 cycles of 35 days.; Drug: Placebo oral tablet; Induction: oral placebo (dose defined in safety run-in phase) 14 days (8-21) (dose will be halved with strong CYP3A inhibitor), up to 2 cycles of 35 days. Consolidation: oral placebo (dose defined in safety run-in phase) 14 days (6-19) (dose will be halved with strong CYP3A inhibitor), up to 4 cycles of 35 days. Maintenance: oral placebo 60mg/day (dose will be halved with strong CYP3A inhibitor), up to 12 cycles of 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival rate	Time from randomization to the date of the occurrence of any of the following events: CR/CRi after 1 or 2 induction cycles, death in CR/CRi or relapse, whichever occurs the first	Through study completion, an average of 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum dose tolerated (MDT) and recommended phase 2 dose (Safety run-in phase)	To determine the maximum dose tolerated (MDT) and the recommended phase 2 dose	At the end of Cycle 1 of Induction and up to 59 days (Safety run-in phase)
Composite Complete Remission (CR/CRi) with minimal residual disease (MRD) negativity	The proportion of subjects with complete response or complete remission with incomplete blood count recovery with Minimal residual disease negative	Through study completion, an average of 5 years
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Adverse events between experimental quizartinib containing schedule and standard arm	Through study completion, an average of 5 years
Disease-free survival	To compare the time from the first documentation of remission to the documentation of disease recurrence or death.	Through study completion, an average of 5 years
Overall survival	The number of days from randomization until death from any cause	Through study completion, an average of 5 years
Cumulative incidence of Relapse	To compare the time from the date of first Complete Response until date of hematological or extramedullary relapse	Through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: PETHEMA Foundation
• Collaborators: Daiichi Sankyo, Inc.; Dynamic Science S.L.
• Investigators: Principal Investigator: Pau Montesinos, Hospital Universitari i Politecnic La Fe

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: September 26, 2019
• First Posted (Actual): September 27, 2019

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: January 20, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Quizartinib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Idarubicin
• Other Study ID Numbers: QUIWI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No