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)

Phase 2

Active, not recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Placebo oral tablet; Drug: Quizartinib; Drug: Cytarabine; Drug: Idarubicin

• Registration Number: NCT04107727
• Lead Sponsor: PETHEMA Foundation

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.

Study Timeline

• Study Start: 2019-09-05
• Study First Submitted: 2019-09-25
• Study First Submitted QC: 2019-09-26
• Study First Posted: 2019-09-27
• Status Verified: 2022-01
• Last Update Submitted: 2022-01-20
• Last Update Posted: 2022-01-21
• Primary Completion: 2024-09
• Study Completion: 2024-09

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 273

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo oral tablet	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.
Quizartinib	Cytarabine	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
Quizartinib	Idarubicin	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
Placebo	Cytarabine	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.
Placebo	Idarubicin	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.
Quizartinib	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

Primary Outcome Measures

Name	Time	Method
Event-free survival rate	Through study completion, an average of 5 years	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

Secondary Outcome Measures

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

Trial Locations

Locations (45)

Hospital Universitari i Politecnic La Fe; 🇪🇸 Valencia, Spain

Hospital Clínico Universitario de Valladolid; 🇪🇸 Valladolid, Spain

Hospital Universitario Miguel Servet; 🇪🇸 Zaragoza, Spain

Hospital Txagorritxu; 🇪🇸 Vitoria, Álava, Spain

Hospital Universitari Germans Trias i Pujol; 🇪🇸 Badalona, Barcelona, Spain

Complejo Hospitalario Universitario de A Coruña; 🇪🇸 Santiago De Compostela, A Coruña, Spain

Hospital General Universitario Santa Lucía; 🇪🇸 Cartagena, Murcia, Spain

Complejo Hospitalario Universitario de Santiago; 🇪🇸 Santiago De Compostela, A Coruña, Spain

Hospital General Univesitario de Castellón; 🇪🇸 Castellón De La Plana, Castellón, Spain

Hospital Universitario Quirón Salud Madrid; 🇪🇸 Pozuelo De Alarcón, Madrid, Spain

Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín; 🇪🇸 Las Palmas De Gran Canaria, Las Palmas, Spain

Hospital Universitario de Galdakao; 🇪🇸 Galdakao, Vizcaya, Spain

Complejo Hospitalario Torrecárdenas; 🇪🇸 Almería, Spain

Hospital Universitario de Canarias; 🇪🇸 La Laguna, Santa Cruz De Tenerife, Spain

Hospital Juan Ramón Jiménez; 🇪🇸 Huelva, Spain

Complejo Hospitalario de Jaén; 🇪🇸 Jaén, Spain

Hospital Ramón y Cajal; 🇪🇸 Madrid, Spain

Hospital Virgen de la Arrixaca; 🇪🇸 Murcia, Spain

Hospital Regional Universitario Málaga; 🇪🇸 Málaga, Spain

Complejo Hospitalario de Pontevedra; 🇪🇸 Pontevedra, Spain

Hospital Universitario Virgen de la Victoria; 🇪🇸 Málaga, Spain

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

Complejo Universitario de Navarra; 🇪🇸 Pamplona, Spain

Hospital Universitario Marques de Valdecilla; 🇪🇸 Santander, Spain

Hospital Nuestra Señora del Prado; 🇪🇸 Talavera De La Reina, Spain

Hospital Clínico Universitario Lozano Blesa; 🇪🇸 Zaragoza, Spain

Hospital Clínico Universitario Valencia; 🇪🇸 Valencia, Spain

Hospital Universitario de Basurto; 🇪🇸 Bilbao, Vizcaya, Spain

Complejo Hospitalario de Albacete; 🇪🇸 Albacete, Spain

Hospital General Universitario de Alicante; 🇪🇸 Alicante, Spain

Complejo Hospitalario Lucus Augusti; 🇪🇸 Lugo, Spain

Fundación Jiménez Díaz; 🇪🇸 Madrid, Spain

Complejo Hospitalario Regional Virgen del Rocío; 🇪🇸 Sevilla, Spain

Complejo Hospitalario de Toledo; 🇪🇸 Toledo, Spain

Hospital Universitario Dr. Peset Aleixandre; 🇪🇸 Valencia, Spain

Complejo Hospitalario Universitario de Vigo; 🇪🇸 Vigo, Pontevedra, Spain

Complejo Hospitalario Regional Reina Sofía; 🇪🇸 Córdoba, Spain

Hospital Universitari Vall Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario de Burgos; 🇪🇸 Burgos, Spain

Hospital Puerta del Mar; 🇪🇸 Cadiz, Spain

Hospital San Pedro de Alcántara; 🇪🇸 Cáceres, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Hospital La Paz; 🇪🇸 Madrid, Spain

Hospital Universitario de Salamanca; 🇪🇸 Salamanca, Spain