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
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
273
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.
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.
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
Time frame: Through study completion, an average of 5 years
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
Time frame: At the end of Cycle 1 of Induction and up to 59 days (Safety run-in phase)
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
Time frame: Through study completion, an average of 5 years
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Adverse events between experimental quizartinib containing schedule and standard arm
Time frame: Through study completion, an average of 5 years
Disease-free survival
To compare the time from the first documentation of remission to the documentation of disease recurrence or death.
Time frame: Through study completion, an average of 5 years
Overall survival
The number of days from randomization until death from any cause
Time frame: Through study completion, an average of 5 years
Cumulative incidence of Relapse
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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.
Induction: Idarubicin IV infusion 12 mg/m2 (days 1-3), up to 2 cycles of 35 days.
Complejo Hospitalario Universitario de A Coruña
Santiago de Compostela, A Coruña, Spain
Complejo Hospitalario Universitario de Santiago
Santiago de Compostela, A Coruña, Spain
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Hospital General Univesitario de Castellón
Castellon, Castellón, Spain
Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
Las Palmas de Gran Canaria, Las Palmas, Spain
Hospital Universitario Quirón Salud Madrid
Pozuelo de Alarcón, Madrid, Spain
Hospital General Universitario Santa Lucía
Cartagena, Murcia, Spain
Complejo Hospitalario Universitario de Vigo
Vigo, Pontevedra, Spain
Hospital Universitario de Canarias
San Cristóbal de La Laguna, Santa Cruz De Tenerife, Spain
Hospital Universitario de Basurto
Bilbao, Vizcaya, Spain
...and 34 more locations
To compare the time from the date of first Complete Response until date of hematological or extramedullary relapse
Time frame: Through study completion, an average of 5 years