Study of Quizartinib in Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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This is a phase 1b, dose escalation, study of quizartinib to evaluate the safety profile, the pharmacokinetics, and the recommended dose of quizartinib for subsequent clinical studies of the combination of quizartinib and induction and consolidation chemotherapy.

Official Title
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Phase 1b, Open-label, Dose Escalation Study of Quizartinib in Combination With Induction and Consolidation Chemotherapy in Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Quizartinib
* Drug: Cytarabine
* Drug: Idarubicin
* Drug: Daunorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No prior treatment for AML (including quizartinib) ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 to 2 Exclusion Criteria: Diagnosis of acute promyelocytic leukemia Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quizartinib 20 mg/day<br>Participants who received 20 mg quizartinib once daily in the morning under fasting conditions. For the Induction phase, cytarabine (100 mg/m^2/day IV) and either idarubicin (12 mg/m^2/day IV infusion) or daunorubicin (60 mg/m^2/day IV) were co-administered with quizartinib. For the Consolidation phase, cytarabine (3.0 g/m^2/12 hours IV) was co-administered with quizartinib. | Drug: Quizartinib<br>* [Induction period, Cycle 1] Once-daily repeated oral administration Day 8 to Day 21. [Induction period, Cycle 2] Once-daily repeated oral administration Day 6 to Day 19. [Consolidation period] Once-daily repeated oral administration Day 6 to Day 19.<br>Drug: Cytarabine<br>* [Induction period, Cycle 1] Once-daily intravenous injection of 100 mg/m^2 cytarabine on Day 1 to 7. [Induction period, Cycle 2] Once-daily intravenous injection of 100 mg/m^2 cytarabine on Day 1 to 5. [Consolidation period] Twice-daily intravenous injection of 3.0 g/m^2 cytarabine at 12-hour intervals on Days 1, 3, and 5.<br>Drug: Idarubicin<br>* Either Idarubicin or Daunorubicin will be used [Induction period, Cycle 1] Once-daily intravenous injection of 12 mg/m^2 idarubicin on Day 1 to 3. [Induction period, Cycle 2] Once-daily intravenous injection of 12 mg/m^2 idarubicin on Day 1 and 2.<br>Drug: Daunorubicin<br>* Either Idarubicin or Daunorubicin will be used [Induction period, Cycle 1] Once-daily intravenous injection of 60mg/m^2 daunorubicin on Day 1 to 3. [Induction period, Cycle 2] Once-daily intravenous injection of 60mg/m^2 daunorubicin on Day 1 and 2.<br>|
| Experimental: Quizartinib 40 mg/day<br>Participants who received 40 mg quizartinib once daily in the morning under fasting conditions. For the Induction phase, cytarabine (100 mg/m^2/day IV) and either idarubicin (12 mg/m^2/day IV infusion) or daunorubicin (60 mg/m^2/day IV) were co-administered with quizartinib. For the Consolidation phase, cytarabine (3.0 g/m^2/12 hours IV) was co-administered with quizartinib. | Drug: Quizartinib<br>* [Induction period, Cycle 1] Once-daily repeated oral administration Day 8 to Day 21. [Induction period, Cycle 2] Once-daily repeated oral administration Day 6 to Day 19. [Consolidation period] Once-daily repeated oral administration Day 6 to Day 19.<br>Drug: Cytarabine<br>* [Induction period, Cycle 1] Once-daily intravenous injection of 100 mg/m^2 cytarabine on Day 1 to 7. [Induction period, Cycle 2] Once-daily intravenous injection of 100 mg/m^2 cytarabine on Day 1 to 5. [Consolidation period] Twice-daily intravenous injection of 3.0 g/m^2 cytarabine at 12-hour intervals on Days 1, 3, and 5.<br>Drug: Idarubicin<br>* Either Idarubicin or Daunorubicin will be used [Induction period, Cycle 1] Once-daily intravenous injection of 12 mg/m^2 idarubicin on Day 1 to 3. [Induction period, Cycle 2] Once-daily intravenous injection of 12 mg/m^2 idarubicin on Day 1 and 2.<br>Drug: Daunorubicin<br>* Either Idarubicin or Daunorubicin will be used [Induction period, Cycle 1] Once-daily intravenous injection of 60mg/m^2 daunorubicin on Day 1 to 3. [Induction period, Cycle 2] Once-daily intravenous injection of 60mg/m^2 daunorubicin on Day 1 and 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Best Responses After a Daily Dose of 20 mg or 40 mg in Combination With Standard Chemotherapy to Japanese Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) | Best response was defined as the best measured complete remission (CR), CR with incomplete hematological recovery (CRi), CR with incomplete platelet recovery (CRp), Partial remission (PR), or No response (NR) in the overall response assessments at all time points after the first dose. | Day 0 to Day 21 of last completed cycle (each cycle 28 days), up to approximately 1 year | 
| Summary of Best Response Rates After the First Oral Dose of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia | Best response was defined as the best measured complete remission (CR), CR with incomplete hematological recovery (CRi), CR with incomplete platelet recovery (CRp), Partial remission (PR), or No response (NR) in the overall response assessments at all time points after the first dose. | Day 0 to Day 21 of last completed cycle (each cycle 28 days), up to approximately 1 year | 
| Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) of Geometric Means of Quizartinib and Active Metabolite (AC886) After Daily Dose of 20 mg or 40 mg Combined With Chemotherapy to Japanese Participants With Newly Diagnosed Acute Myeloid Leukemia | The maximum serum plasma concentration (Cmax) is reported at Induction phase Cycle 1, Day 9 and the maximum serum plasma concentration at steady state (Cmax,ss) is reported at Induction phase Cycle 1, Day 21 for quizartinib, active metabolite AC886, and quizartinib and AC886. | Induction phase Cycle 1, Day 8 to Cycle 1, Day 21 (each cycle 28 days) | 
| Pharmacokinetic Parameter Area Under the Concentration-Time Curve During Dosing Interval of Quizartinib and Metabolite (AC886) After Daily Dose of 20 mg or 40 mg With Chemotherapy to Japanese Participants With Newly Diagnosed Acute Myeloid Leukemia | The area under the plasma concentration-time curve during dosing interval (AUCtau) of geometric means is reported at Induction phase Cycle 1, Day 9 and the area under the plasma concentration-time curve during dosing interval at steady state (AUCtauss) of geometric means are reported at Induction phase Cycle 1, Day 21 for quizartinib, active metabolite AC886, and quizartinib and AC886. | Induction phase Cycle 1, Day 8 to Cycle 1, Day 21 (each cycle 28 days) | 
| Pharmacokinetic Parameter Time of Maximum Plasma Concentration (Tmax) of Quizartinib and the Active Metabolite (AC886) After a Daily Dose of 20 mg or 40 mg Combined With Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | The time of maximum plasma concentration (Tmax) of geometric means is reported at Induction phase Cycle 1, Day 9 and the time of maximum plasma concentration at steady state (Tmax,ss) of geometric means is reported at Induction phase Cycle 1, Day 21 for quizartinib, active metabolite AC886, and quizartinib and AC886. | Induction phase Cycle 1, Day 8 to Cycle 1, Day 21 (each cycle 28 days) | 
| Pharmacokinetic Parameter Metabolite to Parent Ratio (MR) of Active Metabolite (AC886) After a Daily Dose of 20 mg or 40 mg Combined With Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | The metabolite to parent ratio of geometric means for Cmax and AUCtau is reported at Induction phase Cycle 1, Day 9 for active metabolite AC886 is reported. | Induction phase Cycle 1, Day 8 (each cycle 28 days) | 
| Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) of Quizartinib and Active Metabolite (AC886) After a Daily Dose of 20 mg or 40 mg Combined With Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | The trough plasma concentration (Ctrough) of geometric means is reported at Induction phase Cycle 1, Day 21 for serum quizartinib, active metabolite AC886, and quizartinib and AC886. | Induction phase Cycle 1, Day 21 (each cycle 28 days) | 
| Pharmacokinetic Parameter Accumulation Ratio (AR) of Quizartinib and Active Metabolite (AC886) After a Daily Dose of 20 mg or 40 mg Combined With Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | The accumulation ratio of geometric means for Cmax and AUCtau is reported at Induction phase Cycle 1, Day 21 for serum quizartinib, active metabolite AC886, and quizartinib and AC886. | Induction phase Cycle 1, Day 21 (each cycle 28 days) | 
| Number of Participants Treatment-Emergent Adverse Events Reported During Induction Phase After a Daily Dose of 20 mg or 40 mg in Combination With Standard Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that emerges (or worsens) from the first dose of study drug and coadministered drugs to the follow-up visit, 35 days after the last dose of study drug and coadministered drugs, or the start date of new AML post-treatment, whichever was earlier. | Induction phase Cycle 1, Day 1 up to 35 days after last dose in Cycle 2 (each cycle 28 days), up to approximately 1 year | 
| Number of Participants Treatment-Emergent Adverse Events Reported During Consolidation Phase After a Daily Dose of 20 mg or 40 mg in Combination With Standard Chemotherapy to Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) | A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that emerges (or worsens) from the first dose of study drug and coadministered drugs to the follow-up visit, 35 days after the last dose of study drug and coadministered drugs, or the start date of new AML post-treatment, whichever was earlier. | Consolidation phase Cycle 1, Day 1 up to 35 days after last dose (each cycle 28 days), up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, phase 1, hematology, malignancy, newly diagnosed