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)

• Sponsor: PETHEMA Foundation (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT04107727
• Collaborator: Dynamic Science S.L. (Industry), Daiichi Sankyo, Inc. (Industry)
• Enrollment: 273
• Locations: 45
• Arms: 2
• Anticipated Duration (Months): 59.9
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Quizartinib; Drug: Placebo oral tablet; Drug: Cytarabine; Drug: Idarubicin	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 273 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Safety run-in phase: multicenter, prospective, open-label. Phase II: multicenter, prospective, randomized, placebo-controlled, double-blindedSafety run-in phase: multicenter, prospective, open-label. Phase II: multicenter, prospective, randomized, placebo-controlled, double-blinded
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Subjects will be randomized into 1 of the 2 treatment groups (quizartinib or placebo) in a 2:1 ratio. The randomization will be stratified by age (<60 vs. ≥60 years old) at the time of diagnosis of AML. Neither the subjects nor any of the Investigators, Sponsor, or contract research organizations (CROs) will be aware of the treatments received. An independent biostatistician, not otherwise part of the study team, will generate the randomization schedule.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 5, 2019
• Anticipated Primary Completion Date: Sep 1, 2024
• Anticipated Study Completion Date: Sep 1, 2024

Arms and Interventions

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: 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.; 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.

Outcome Measures

Primary Outcome Measures

1. 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

1. 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

2. 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

3. 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

4. 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.

5. Overall survival [Through study completion, an average of 5 years]

   The number of days from randomization until death from any cause

6. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. Leukapheresis d) Treatment for hyperleukocytosis with hydroxyurea

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

2. 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.

1. Known active and not controlled hepatitis B or hepatitis C infection. In the event of a positive viral load, please consult with the Sponsor

2. Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)

3. 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

4. Serum creatinine ≥ 250 μmol/l (≥ 2.5 mg/dL) (unless it is attributable to AML activity)

5. Bilirubin, alkaline phosphatase, or Serum glutamic oxaloacetic transaminase (SGOT) > 3 times the normal upper limit (unless it is attributable to AML activity)

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

7. Symptomatic bradycardia of fewer than 50 beats per minute, unless the subject has a pacemaker;

8. QT Comparison of Fridericia's (QTcF) >450 msec at Screening. Note: QTcF will be derived from the mean of triplicate readings;

9. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);

10. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥ 110 mmHg;

11. History of clinically relevant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes)

12. 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)

13. An ejection fraction <45%

14. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening

15. History of New York Heart Association Class 3 or 4 heart failure

16. Right bundle branch and left anterior hemiblock (bifascicular block), complete left bundle branch block

17. History of hypersensitivity to any excipients in the quizartinib/placebo tablets

18. Females who are pregnant or breastfeeding

19. Any patients with known significant impairment in gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of quizartinib.

20. Active acute or chronic Graft-Versus-Host-Disease (GVHD) requiring prednisone >10 mg or equivalent corticosteroid daily.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Complejo Hospitalario Universitario de A Coruña	Santiago De Compostela	A Coruña	Spain	15706
2	Complejo Hospitalario Universitario de Santiago	Santiago De Compostela	A Coruña	Spain	15706
3	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
4	Hospital General Univesitario de Castellón	Castellón De La Plana	Castellón	Spain	12004
5	Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria	Las Palmas	Spain	35020
6	Hospital Universitario Quirón Salud Madrid	Pozuelo De Alarcón	Madrid	Spain	28223
7	Hospital General Universitario Santa Lucía	Cartagena	Murcia	Spain	30200
8	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra	Spain	36312
9	Hospital Universitario de Canarias	La Laguna	Santa Cruz De Tenerife	Spain	38320
10	Hospital Universitario de Basurto	Bilbao	Vizcaya	Spain	48013
11	Hospital Universitario de Galdakao	Galdakao	Vizcaya	Spain	48960
12	Complejo Hospitalario de Albacete	Albacete		Spain	02006
13	Hospital General Universitario de Alicante	Alicante		Spain	03010
14	Complejo Hospitalario Torrecárdenas	Almería		Spain	04004
15	Hospital Universitari Vall Hebron	Barcelona		Spain	08035
16	Hospital Universitario de Burgos	Burgos		Spain	09006
17	Hospital Puerta del Mar	Cadiz		Spain
18	Hospital San Pedro de Alcántara	Cáceres		Spain	10003
19	Complejo Hospitalario Regional Reina Sofía	Córdoba		Spain	14004
20	Hospital Juan Ramón Jiménez	Huelva		Spain	21005
21	Complejo Hospitalario de Jaén	Jaén		Spain	23007
22	Complejo Hospitalario Lucus Augusti	Lugo		Spain	27003
23	Fundación Jiménez Díaz	Madrid		Spain	28040
24	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
25	Hospital Clínico San Carlos	Madrid		Spain
26	Hospital La Paz	Madrid		Spain
27	Hospital Ramón y Cajal	Madrid		Spain
28	Hospital Virgen de la Arrixaca	Murcia		Spain
29	Hospital Regional Universitario Málaga	Málaga		Spain	29010
30	Hospital Universitario Virgen de la Victoria	Málaga		Spain	29010
31	Hospital Universitario Central de Asturias	Oviedo		Spain	33006
32	Complejo Universitario de Navarra	Pamplona		Spain	31008
33	Complejo Hospitalario de Pontevedra	Pontevedra		Spain	36071
34	Hospital Universitario de Salamanca	Salamanca		Spain	37007
35	Hospital Universitario Marques de Valdecilla	Santander		Spain	39008
36	Complejo Hospitalario Regional Virgen del Rocío	Sevilla		Spain	41013
37	Hospital Nuestra Señora del Prado	Talavera De La Reina		Spain
38	Complejo Hospitalario de Toledo	Toledo		Spain	45004
39	Hospital Clínico Universitario Valencia	Valencia		Spain	46010
40	Hospital Universitario Dr. Peset Aleixandre	Valencia		Spain	46017
41	Hospital Universitari i Politecnic La Fe	Valencia		Spain	46026
42	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47003
43	Hospital Clínico Universitario Lozano Blesa	Zaragoza		Spain	50009
44	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
45	Hospital Txagorritxu	Vitoria	Álava	Spain	01009

Sponsors and Collaborators

• PETHEMA Foundation
• Dynamic Science S.L.
• Daiichi Sankyo, Inc.

Investigators

• Principal Investigator: Pau Montesinos, Hospital Universitari i Politecnic La Fe

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PETHEMA Foundation
• ClinicalTrials.gov Identifier: NCT04107727
• Other Study ID Numbers: QUIWI
• First Posted: Sep 27, 2019
• Last Update Posted: Jan 21, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by PETHEMA Foundation: Quizartinib
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Idarubicin

Study Results

No Results Posted as of Jan 21, 2022