A Clinical Trial to Assess the Efficacy and Safety of the Combination of a Drug Call Quizartinib With Chemotherapy (FLAG-IDA) in Patients With Acute Myeloid Leukemia That Has Not Responded to the First Treatment or That Has Returned After the First Treatment

Sponsor

PETHEMA Foundation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04112589

Collaborator

Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company (Industry), Syntax for Science, S.L (Industry)

Enrollment

Locations

Arms

47.2

Anticipated Duration (Months)

3.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, prospective, non-randomized, Phase I-II trial to assess the efficacy and safety of the combination of oral quizartinib and FLAG-IDA chemotherapy schedule (FLAG-QUIDA regimen) in first relapsed/refractory AML (acute myeloid leukemia) patients.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Quizartinib Drug: Fludarabine Drug: Cytarabine Drug: Idarubicin Drug: glycosylated G-CSF	Phase 1/Phase 2

Detailed Description

Patients of approximately 20 sites (in Spain and Portugal) will receive FLAG-QUIDA regimen followed by transplantation, when possible, with up to 3 optional consolidation cycles. All patients in CR/CRi (complete remission / complete remission with incomplete hematologic recovery) will receive a maintenance schedule.

A Phase I (dose escalation) will be performed at 40 mg x 14 days of quizartinib in the first 3 patients, and if no dose-limiting toxicity (DLT) is observed, the next cohort of patients will receive 60 mg x 14 days. There is also the possibility of de-escalation cohorts at 60 mg x 7 days and at 40 mg x 7 days. Patients participating in the Phase I will receive the allocated dose level, and therefore, they must not receive strong CYP3A4 inhibitors concomitantly with quizartinib The Phase II will include 68 patients treated at the RP2D (recommended phase 2 dose). A 1-year maintenance schedule starting at 30 mg will be increased to 60 mg/day if appropriate.

Patients will be followed up for a minimum period of 1 year since the first visit of the last patient included.

Study Design

Study Type:

Interventional

Actual Enrollment :

63 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

The study consists of a dose escalation-dose finding part (phase I) and a phase II part. Subjects will have an induction of 1 cycle, by an alloSCT (allogeneic hematopoietic stem cell transplantation) in CR/CRi, when possible, with up to 3 optional HiDAC (high dose Cytarabine ) consolidation cycles. All patients in CR/CRi will receive a maintenance schedule (12 months, 12 cycles). The phase I portion will progress from starting level dose 1 (40mg 14 days) to level dose 2 (60 mg 14 days). De-escalation to level dose -1 (60mg 7 days) or level dose -2 (40mg 7 days) may be necessary to be explored. Once the RP2D is established, the phase II will start.The study consists of a dose escalation-dose finding part (phase I) and a phase II part. Subjects will have an induction of 1 cycle, by an alloSCT (allogeneic hematopoietic stem cell transplantation) in CR/CRi, when possible, with up to 3 optional HiDAC (high dose Cytarabine ) consolidation cycles. All patients in CR/CRi will receive a maintenance schedule (12 months, 12 cycles). The phase I portion will progress from starting level dose 1 (40mg 14 days) to level dose 2 (60 mg 14 days). De-escalation to level dose -1 (60mg 7 days) or level dose -2 (40mg 7 days) may be necessary to be explored. Once the RP2D is established, the phase II will start.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Prospective, Non-randomized, Phase I-II Trial to Assess the Efficacy and Safety of the Combination of Oral Quizartinib and the FLAG-IDA Chemotherapy Regimen in First Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Patients

Actual Study Start Date :

Dec 26, 2019

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Level dose 1 - 40mg, 14 days Patients will receive an induction cycle (40mg Quizartinib for 14 days) followed by 1-3 consolidation cycles (Quizartinib at day 6) [with or without allogenic stem cell transplantation]- Responders will have 12 months maintenance starting at 30mg/day Quizartinib will be increased to 60 mg/day after 15 days if appropriate.	Drug: Quizartinib Quizartinib at different doses in the phase I (40mg-14 days; 60mg-14 days; 60mg-7days, 40mg-7days). RP2D in the phase II part. Drug: Fludarabine 30 mg/m2 intravenous days 1 to 4 of the cycle Drug: Cytarabine 2 g/m 2 intravenous days 1 to 4 (1 g/m2 in patients older than 59) of the cycle Drug: Idarubicin 10 mg/ 2 intravenous days 1 to 3 of the cycle Drug: glycosylated G-CSF daily dose of 300 mcg/m 2 , from day -1 until day 5 of the cycle
Experimental: Level dose 2 - 60mg, 14 days Patients will receive an induction cycle (60mg Quizartinib for 14 days) followed by 1-3 consolidation cycles (Quizartinib at day 6) [with or without allogenic stem cell transplantation]- Responders will have 12 months maintenance starting at 30mg/day Quizartinib will be increased to 60 mg/day after 15 days if appropriate.	Drug: Quizartinib Quizartinib at different doses in the phase I (40mg-14 days; 60mg-14 days; 60mg-7days, 40mg-7days). RP2D in the phase II part. Drug: Fludarabine 30 mg/m2 intravenous days 1 to 4 of the cycle Drug: Cytarabine 2 g/m 2 intravenous days 1 to 4 (1 g/m2 in patients older than 59) of the cycle Drug: Idarubicin 10 mg/ 2 intravenous days 1 to 3 of the cycle Drug: glycosylated G-CSF daily dose of 300 mcg/m 2 , from day -1 until day 5 of the cycle
Experimental: Level dose -1 - 60mg 7days Patients will receive an induction cycle (60mg Quizartinib for 7 days) followed by 1-3 consolidation cycles (Quizartinib at day 6) [with or without allogenic stem cell transplantation]- Responders will have 12 months maintenance starting at 30mg/day Quizartinib will be increased to 60 mg/day after 15 days if appropriate.	Drug: Quizartinib Quizartinib at different doses in the phase I (40mg-14 days; 60mg-14 days; 60mg-7days, 40mg-7days). RP2D in the phase II part. Drug: Fludarabine 30 mg/m2 intravenous days 1 to 4 of the cycle Drug: Cytarabine 2 g/m 2 intravenous days 1 to 4 (1 g/m2 in patients older than 59) of the cycle Drug: Idarubicin 10 mg/ 2 intravenous days 1 to 3 of the cycle Drug: glycosylated G-CSF daily dose of 300 mcg/m 2 , from day -1 until day 5 of the cycle
Experimental: Level dose -2 - 40mg 7 days Patients will receive an induction cycle (40mg Quizartinib for 7days) followed by 1-3 consolidation cycles (Quizartinib at day 6) [with or without allogenic stem cell transplantation]- Responders will have 12 months maintenance starting at 30mg/day Quizartinib will be increased to 60 mg/day after 15 days if appropriate.	Drug: Quizartinib Quizartinib at different doses in the phase I (40mg-14 days; 60mg-14 days; 60mg-7days, 40mg-7days). RP2D in the phase II part. Drug: Fludarabine 30 mg/m2 intravenous days 1 to 4 of the cycle Drug: Cytarabine 2 g/m 2 intravenous days 1 to 4 (1 g/m2 in patients older than 59) of the cycle Drug: Idarubicin 10 mg/ 2 intravenous days 1 to 3 of the cycle Drug: glycosylated G-CSF daily dose of 300 mcg/m 2 , from day -1 until day 5 of the cycle

Outcome Measures

Primary Outcome Measures

RP2D finding [1 cycle (4 weeks)]
Maximum Tolerated dose of the combination of quizartinib a FLAG-IDA regimen
Rate CR/CRi [3 years]
To assess the rate of CR/CRi after one cycle of FLAG-QUIDA

Secondary Outcome Measures

Disease-free survival (DFS) [3 years]
time from the first documentation of remission to the documentation of disease recurrence or death
Overall survival (OS) [3 years]
Number of days from randomization until death from any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. Informed consent form must be signed by the patient and the Investigator.
Patients aged ≥ 18 years old and ≤70 years old at the time of screening.
First R/R AML defined as:

First relapse after frontline intensive chemotherapy (with or without prior alloSCT), irrespectively of the duration of the first CR. Patients previously treated with a FLT3 inhibitor different from quizartinib, can be included.
First refractory disease (defined as patients not achieving at least a PR after first induction cycle and/or not achieving CR/CRi after first 2 cycles). Patients previously treated with a FLT3 inhibitor different from quizartinib, can be included.

Non-APL AML.
Considered for intensive approach as per Investigator judgment.
ECOG 0-2.
No contraindications for quizartinib.
No contraindications for intensive chemotherapy.
No severe organ function abnormalities.
No active relevant GVHD.
For the Phase II, FLT3-ITD patients will represent 50% of the study cohort (FLT3-TKD are not excluded but included in the FLT3-ITD-WT group).
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 6 months following the last dose of investigational drug or cytarabine, whichever is later.
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 6 months following the last dose of investigational drug or cytarabine, whichever is later.

Exclusion Criteria:

Patients with genetic diagnosis of acute promyelocytic leukemia.
Blastic phase of bcr/abl chronic myeloid leukemia.
Patients with other neoplastic disease, for whom the Investigator has 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 if they are on a stable dose for at least 2 weeks prior to first dose.
Presence of any severe psychiatric disease or physical condition/comorbidity that, according to the physician´s criteria, contraindicates the inclusion of the patient in the clinical trial
Serum creatinine ≥ 250 μmol/l (≥ 2.5 mg/dL) (unless it is attributable to AML activity).
Bilirubin, alkaline phosphatase, or SGOT >3 times the upper normal limit (unless it is attributable to AML activity).
Uncontrolled or significant cardiovascular disease, including any of the following:

Symptomatic bradycardia of less than 50 beats per minute, unless the subject has a pacemaker.
QTcF >450 ms at screening. Note: QTcF will be derived from the mean of triplicate readings.
Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome)
History of clinically relevant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes).
History of 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).
History of uncontrolled angina pectoris or myocardial infarction within 6months prior to Screening.
History of New York Heart Association Class 3 or 4 heart failure.
Complete left bundle branch block.
Right bundle branch and left anterior hemiblock (bifascicular block)
Infarction (MI) within 3 months.
Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥ 110 mmHg
A previously known left ventricle ejection fraction <45%

Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral.
Active hepatitis B or hepatitis C infection.
Previously known and documented human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study).
Active acute or chronic GVHD requiring prednisone >10 mg or equivalent corticosteroid daily
Any patients with known significant impairment in gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of quizartinib
History of hypersensitivity to any excipients in the quizartinib tablets.
Females who are pregnant or breastfeeding.
Isolated extramedullary R/R AML.
Only applicable to patients screened after the first cohort of 34 patients of the Phase II has been achieved (e.g., FLT3-ITD negative): patients must have a confirmation of FLT3-ITD status at relapse, and this must correspond to the non-achieved cohort (e.g. FLT3-ITD positive).

Contacts and Locations

Locations

	Site	City	Country
1	Hospital General Universitario de Alicante	Alicante	Spain
2	Institut Català D'Oncologia-Hospital Germans Trias I Pujol	Badalona	Spain
3	Institut Català D'Oncologia-Hospital Duran I Reynals	Bellvitge	Spain
4	Hospital Universitario Puerta Del Mar	Cadiz	Spain
5	Complexo Hospitalario Universitario A Coruña	Coruña	Spain
6	Hospital San Pedro de Alcántara	Cáceres	Spain
7	Hospital Universitario Reina Sofía	Córdoba	Spain
8	ICO Girona - Hospital Josep Trueta	Girona	Spain
9	Hospital Universitario de Jerez de La Frontera	Jerez De La Frontera	Spain
10	Complejo Hospitalario de Gran Canaria Dr. Negrin	Las Palmas De Gran Canaria	Spain
11	Complejo Hospitalario Universitario Insular-Materno Infantil	Las Palmas De Gran Canaria	Spain
12	Hospital Ramón Y Cajal	Madrid	Spain
13	Hospital Universitario 12 de Octubre	Madrid	Spain
14	Hospital Universitario Virgen de La Victoria	Málaga	Spain
15	Hospital Universitario Central de Asturias	Oviedo	Spain
16	Hospital Universitari Son Espases	Palma De Mallorca	Spain
17	Clínica Universitaria de Navarra	Pamplona	Spain
18	Hospital Universitario Virgen Del Rocío	Sevilla	Spain
19	Hospital Universitari Joan Xxiii de Tarragona	Tarragona	Spain
20	Hospital Universitari i Politècnic La Fe	Valencia	Spain