Clinical trial NCT04107727: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Quizartinib
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
Collaborators: name: Dynamic Science S.L.
name: Daiichi Sankyo
First posted: 2019-09-27
Enrollment: 273
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Safety run-in phase: multicenter, prospective, open-label.

Phase II: multicenter, prospective, randomized, placebo-controlled, double-blinded
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Event-free survival rate
timeFrame: Through study completion, an average of 5 years
Secondary outcomes:
measure: Maximum dose tolerated (MDT) and recommended phase 2 dose (Safety run-in phase)
timeFrame: At the end of Cycle 1 of Induction and up to 59 days (Safety run-in phase)
measure: Composite Complete Remission (CR/CRi) with minimal residual disease (MRD) negativity
timeFrame: Through study completion, an average of 5 years
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Through study completion, an average of 5 years
measure: Disease-free survival
timeFrame: Through study completion, an average of 5 years
measure: Overall survival
timeFrame: Through study completion, an average of 5 years
measure: Cumulative incidence of Relapse
timeFrame: Through study completion, an average of 5 years
Other outcomes:
Locations:
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de A Coruña
state: A Coruña
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
state: A Coruña
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Castellón De La Plana
country: Spain
facility: Hospital General Univesitario de Castellón
state: Castellón
city: Las Palmas De Gran Canaria
country: Spain
facility: Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
state: Las Palmas
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Universitario Quirón Salud Madrid
state: Madrid
city: Cartagena
country: Spain
facility: Hospital General Universitario Santa Lucía
state: Murcia
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
state: Pontevedra
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Santa Cruz De Tenerife
city: Bilbao
country: Spain
facility: Hospital Universitario de Basurto
state: Vizcaya
city: Galdakao
country: Spain
facility: Hospital Universitario de Galdakao
state: Vizcaya
city: Albacete
country: Spain
facility: Complejo Hospitalario de Albacete
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Almería
country: Spain
facility: Complejo Hospitalario Torrecárdenas
city: Barcelona
country: Spain
facility: Hospital Universitari Vall Hebron
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Cadiz
country: Spain
facility: Hospital Puerta del Mar
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: Córdoba
country: Spain
facility: Complejo Hospitalario Regional Reina Sofía
city: Huelva
country: Spain
facility: Hospital Juan Ramón Jiménez
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Lugo
country: Spain
facility: Complejo Hospitalario Lucus Augusti
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital La Paz
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Murcia
country: Spain
facility: Hospital Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Regional Universitario Málaga
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Pamplona
country: Spain
facility: Complejo Universitario de Navarra
city: Pontevedra
country: Spain
facility: Complejo Hospitalario de Pontevedra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Sevilla
country: Spain
facility: Complejo Hospitalario Regional Virgen del Rocío
city: Talavera De La Reina
country: Spain
facility: Hospital Nuestra Señora del Prado
city: Toledo
country: Spain
facility: Complejo Hospitalario de Toledo
city: Valencia
country: Spain
facility: Hospital Clínico Universitario Valencia
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset Aleixandre
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
state: Álava
Study officials:
affiliation: Hospital Universitari i Politecnic La Fe
name: Pau Montesinos
role: PRINCIPAL_INVESTIGATOR
References: