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

NCT04112589 | Unknown Phase 1

• 1 other identifier: FLAG-QUIDA
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 20

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• RP2D finding

  Maximum Tolerated dose of the combination of quizartinib a FLAG-IDA regimen

  1 cycle (4 weeks)

• Rate CR/CRi

  To assess the rate of CR/CRi after one cycle of FLAG-QUIDA

  3 years

Secondary Outcomes (2)

• Disease-free survival (DFS)

  3 years

• Overall survival (OS)

  3 years

Study Arms (4)

Level dose 1 - 40mg, 14 days

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: glycosylated G-CSF

Level dose 2 - 60mg, 14 days

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: glycosylated G-CSF

Level dose -1 - 60mg 7days

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: glycosylated G-CSF

Level dose -2 - 40mg 7 days

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: glycosylated G-CSF

Interventions

Quizartinib DRUG

Quizartinib at different doses in the phase I (40mg-14 days; 60mg-14 days; 60mg-7days, 40mg-7days). RP2D in the phase II part.

Level dose -1 - 60mg 7days; Level dose -2 - 40mg 7 days; Level dose 1 - 40mg, 14 days; Level dose 2 - 60mg, 14 days

Fludarabine DRUG

30 mg/m2 intravenous days 1 to 4 of the cycle

Level dose -1 - 60mg 7days; Level dose -2 - 40mg 7 days; Level dose 1 - 40mg, 14 days; Level dose 2 - 60mg, 14 days

Cytarabine DRUG

2 g/m 2 intravenous days 1 to 4 (1 g/m2 in patients older than 59) of the cycle

Level dose -1 - 60mg 7days; Level dose -2 - 40mg 7 days; Level dose 1 - 40mg, 14 days; Level dose 2 - 60mg, 14 days

Idarubicin DRUG

10 mg/ 2 intravenous days 1 to 3 of the cycle

Level dose -1 - 60mg 7days; Level dose -2 - 40mg 7 days; Level dose 1 - 40mg, 14 days; Level dose 2 - 60mg, 14 days

glycosylated G-CSF DRUG

daily dose of 300 mcg/m 2 , from day -1 until day 5 of the cycle

Level dose -1 - 60mg 7days; Level dose -2 - 40mg 7 days; Level dose 1 - 40mg, 14 days; Level dose 2 - 60mg, 14 days

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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)

Sponsors & Collaborators

• PETHEMA Foundation: lead
• Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company: collaborator
• Syntax for Science, S.L: collaborator

Study Sites (20)

Complexo Hospitalario Universitario A Coruña

A Coruña, Spain

Location

Hospital General Universitario de Alicante

Alicante, Spain

Location

Institut Català D'Oncologia-Hospital Germans Trias I Pujol

Badalona, Spain

Location

Institut Català D'Oncologia-Hospital Duran I Reynals

Bellvitge, Spain

Location

Hospital Universitario Puerta Del Mar

Cadiz, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Spain

Location

ICO Girona - Hospital Josep Trueta

Girona, Spain

Location

Hospital Universitario de Jerez de La Frontera

Jerez de la Frontera, Spain

Location

Complejo Hospitalario de Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, Spain

Location

Complejo Hospitalario Universitario Insular-Materno Infantil

Las Palmas de Gran Canaria, Spain

Location

Hospital Ramón Y Cajal

Madrid, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Virgen de La Victoria

Málaga, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, Spain

Location

Hospital Universitari Son Espases

Palma de Mallorca, Spain

Location

Clínica Universitaria de Navarra

Pamplona, Spain

Location

Hospital Universitario Virgen Del Rocío

Seville, Spain

Location

Hospital Universitari Joan Xxiii de Tarragona

Tarragona, Spain

Location

Hospital Universitari i Politècnic La Fe

Valencia, Spain

Location

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• Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74. doi: 10.1182/blood-2009-07-235358. Epub 2009 Oct 30.

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• Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood. 2013 Feb 14;121(7):1077-82. doi: 10.1182/blood-2012-08-234492. Epub 2012 Dec 14.

  PMID: 23243288 BACKGROUND

• Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia. 2000 Mar;14(3):476-9. doi: 10.1038/sj.leu.2401568.

  PMID: 10720145 BACKGROUND

• Yavuz S, Paydas S, Disel U, Sahin B. IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. Am J Ther. 2006 Sep-Oct;13(5):389-93. doi: 10.1097/01.mjt.0000181690.21601.09.

  PMID: 16988532 BACKGROUND

• Pastore D, Specchia G, Carluccio P, Liso A, Mestice A, Rizzi R, Greco G, Buquicchio C, Liso V. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003 Apr;82(4):231-5. doi: 10.1007/s00277-003-0624-2. Epub 2003 Mar 15.

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• de la Rubia J, Regadera A, Martin G, Cervera J, Sanz G, Martinez J, Jarque I, Garcia I, Andreu R, Moscardo F, Jimenez C, Molla S, Benlloch L, Sanz M. FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. Leuk Res. 2002 Aug;26(8):725-30. doi: 10.1016/s0145-2126(02)00003-6.

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• Kim H, Park JH, Lee JH, Lee JH, Joo YD, Lee WS, Bae SH, Mo Ryoo H, Lee KH; Cooperative Study Group A for Hematology. Continuous infusion of intermediate-dose cytarabine and fludarabine with idarubicin for patients younger than 60 years with resistant acute myeloid leukemia: a prospective, multicenter phase II study. Am J Hematol. 2009 Mar;84(3):161-6. doi: 10.1002/ajh.21351.

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• Bergua JM, Montesinos P, Martinez-Cuadron D, Fernandez-Abellan P, Serrano J, Sayas MJ, Prieto-Fernandez J, Garcia R, Garcia-Huerta AJ, Barrios M, Benavente C, Perez-Encinas M, Simiele A, Rodriguez-Macias G, Herrera-Puente P, Rodriguez-Veiga R, Martinez-Sanchez MP, Amador-Barciela ML, Riaza-Grau R, Sanz MA; PETHEMA group. A prognostic model for survival after salvage treatment with FLAG-Ida +/- gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol. 2016 Sep;174(5):700-10. doi: 10.1111/bjh.14107. Epub 2016 Apr 26.

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• Cortes J, Perl AE, Dohner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Kramer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. doi: 10.1016/S1470-2045(18)30240-7. Epub 2018 May 31.

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• Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. doi: 10.1200/JCO.2013.48.8783. Epub 2013 Sep 3.

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• Chen Y, Pan Y, Guo Y, Zhao W, Ho WT, Wang J, Xu M, Yang FC, Zhao ZJ. Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia. Stem Cell Investig. 2017 Jun 2;4:48. doi: 10.21037/sci.2017.05.04. eCollection 2017.

  PMID: 28607922 BACKGROUND

• Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.

  PMID: 14673054 BACKGROUND

• Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2004 Aug 15;22(16):3432-3. doi: 10.1200/JCO.2004.99.116. No abstract available.

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• Montesinos P, Lorenzo I, Martin G, Sanz J, Perez-Sirvent ML, Martinez D, Orti G, Algarra L, Martinez J, Moscardo F, de la Rubia J, Jarque I, Sanz G, Sanz MA. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008 Jan;93(1):67-74. doi: 10.3324/haematol.11575.

  PMID: 18166787 BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

quizartinib; fludarabine; Cytarabine; Idarubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Pau Montesinos, MD

  Trial Coordinator, Institution Contact

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 30, 2019
• First Posted: October 2, 2019
• Study Start: December 26, 2019
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: March 14, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (20)