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)

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04107727
• Other study ID #: QUIWI
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 5, 2019
• Est. completion date: September 2024

Study information

• Verified date: January 2022
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 273
• Est. completion date: September 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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.
• 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.
• 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.
• Idarubicin
Induction: Idarubicin IV infusion 12 mg/m2 (days 1-3), up to 2 cycles of 35 days.

Locations

Country	Name	City	State
Spain	Complejo Hospitalario de Albacete	Albacete
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Complejo Hospitalario Torrecárdenas	Almería
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Universitari Vall Hebron	Barcelona
Spain	Hospital Universitario de Basurto	Bilbao	Vizcaya
Spain	Hospital Universitario de Burgos	Burgos
Spain	Hospital San Pedro de Alcántara	Cáceres
Spain	Hospital Puerta del Mar	Cadiz
Spain	Hospital General Universitario Santa Lucía	Cartagena	Murcia
Spain	Hospital General Univesitario de Castellón	Castellón De La Plana	Castellón
Spain	Complejo Hospitalario Regional Reina Sofía	Córdoba
Spain	Hospital Universitario de Galdakao	Galdakao	Vizcaya
Spain	Hospital Juan Ramón Jiménez	Huelva
Spain	Complejo Hospitalario de Jaén	Jaén
Spain	Hospital Universitario de Canarias	La Laguna	Santa Cruz De Tenerife
Spain	Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria	Las Palmas
Spain	Complejo Hospitalario Lucus Augusti	Lugo
Spain	Fundación Jiménez Díaz	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital La Paz	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Regional Universitario Málaga	Málaga
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Complejo Universitario de Navarra	Pamplona
Spain	Complejo Hospitalario de Pontevedra	Pontevedra
Spain	Hospital Universitario Quirón Salud Madrid	Pozuelo De Alarcón	Madrid
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Marques de Valdecilla	Santander
Spain	Complejo Hospitalario Universitario de A Coruña	Santiago De Compostela	A Coruña
Spain	Complejo Hospitalario Universitario de Santiago	Santiago De Compostela	A Coruña
Spain	Complejo Hospitalario Regional Virgen del Rocío	Sevilla
Spain	Hospital Nuestra Señora del Prado	Talavera De La Reina
Spain	Complejo Hospitalario de Toledo	Toledo
Spain	Hospital Clínico Universitario Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Spain	Hospital Universitario Dr. Peset Aleixandre	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra
Spain	Hospital Txagorritxu	Vitoria	Álava
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (3)

Lead Sponsor	Collaborator
PETHEMA Foundation	Daiichi Sankyo, Inc., Dynamic Science S.L.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall survival	The number of days from randomization until death from any cause	Through study completion, an average of 5 years
Secondary	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