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)
273
45
2
59.9
6.1
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
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
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jan 21, 2022