A Phase I Study of AC220 in Patients With Relapsed/Refractory Acute Myeloid Leukemia Regardless of FLT3 Status

Study Overview
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Brief Summary
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Patients received oral AC220 daily for 14 days to study the side effects, tolerability and best dose for treating relapsed or refractory acute myeloid leukemia, regardless of FLT3 status.

Detailed Description
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This is a multi-center clinical study conducted in the USA and two international sites. This open-label, dose escalation study was designed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered AC220 as a single agent given daily for 14 days. Cohorts of 3 patients received AC220 until dose limiting toxicity was noted (DLT). At that point cohorts expanded to 6 patients until MTD was determined. Patients not experiencing DLT or significant disease progression at Day 15 may have continued receiving AC220 at the discretion of the Investigator and Sponsor. FLT3 positive and negative patients were allowed to participate.

Official Title
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Phase I Open-Label, Sequential Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AC220 When Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Leukemia, Myelodysplastic Syndrome, AML, MDS

Intervention / Treatment
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* Drug: AC220


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females age ≥ 18 years; Histopathologically documented primary or secondary AML, as defined by WHO criteria (Jaffe et al, 2001), confirmed by pathology review at treating institution, meeting at least one of the following: Refractory to at least 1 cycle of induction chemotherapy, or Relapsed after at least 1 cycle of induction chemotherapy, or Patient is not, according to the clinical judgment of the Principal Investigator, a candidate for induction chemotherapy due to age, comorbidity, or other factors; Patients for whom no standard therapies are anticipated to result in a durable remission, or who have failed potentially curative therapy, or who refuse standard therapy or patients for whom there is no known therapy of documented treatment benefit; Eastern Cooperative Oncology Group (ECOG) performance status of 0-3; In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration should be at least 2 weeks for cytotoxic agents (other than hydroxyurea, per Section 8.8), or at least 5 half-lives for noncytotoxic agents; Persistent chronic clinically significant toxicities from prior chemotherapy or surgery must be less than Grade 2; Serum creatinine ≤ 2.0 mg/dL; Total serum bilirubin ≤ 1.5 × ULN unless considered due to Gilbert's syndrome or leukemic organ involvement; Serum AST or ALT ≤ 3.0 × ULN unless considered due to leukemic organ involvement; Females of childbearing potential must have a negative pregnancy test (urine β-hCG); Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study; Written informed consent must be provided. Exclusion Criteria: Histologic diagnosis of acute promyelocytic leukemia; Clinically active central nervous system leukemia; Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3); Bone marrow transplant within 2 months prior to study; Active, uncontrolled infection; Major surgery within 4 weeks prior to study; Radiation therapy within 4 weeks prior to, or concurrent with, study; Human immunodeficiency virus positivity; Active hepatitis B or C or other active liver disease; Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential; Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the judgment of the Principal Investigator, could jeopardize patient safety or interfere with the objectives of the study.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AC220<br>Determine safety, tolerability and pharmacokinetic (PK) parameters of AC220 | Drug: AC220<br>* Powder in bottle formulation supplied as 50mg or 350 mg in glass, crimped serum vials. Requires reconstitution by a pharmacist, and must be stored securely and protected from light.<br>* Other names: Quizartinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Treatment Related Adverse Events Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia |  | Baseline up to 30 days post last dose | 
| Number of Participants With Treatment-emergent Treatment-related Grade 3 or 4 Adverse Events By At Least 10% of All Participants By Dose Group Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia |  | Baseline up to 30 days post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving a Best Disease Response by Dose Cohort in Terms of Progressive Disease Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia | Progressive disease response criteria included doubling of blast count % in bone marrow (biopsy or aspirate) from baseline; considering measurements starting on Study Day 15, doubling of blast count % in blood from baseline; death determined to be related to disease or disease progression; and investigator reported disease progression. | Baseline up to 28 days after the last dose, up to approximately 3 years | 
| Number of Participants Achieving a Best Disease Response by Dose Cohort in Terms of Best Overall Response Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia | Complete Response (CR) response criteria included either a post-baseline bone marrow (BM) biopsy or aspiration % blasts <5%, absolute neutrophil count (ANC) >1×10^9/L and platelet count >100×10^9/L on the same date as the qualifying BM assessment. CRp response included all CR criteria met, except participant did not experience a platelet recovery (ANC recovery required). CRi response included a qualifying BM result, but not an ANC recovery. Participants may or may not have had a platelet recovery and were not required to be transfusion independent. Partial remission (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline to a post-baseline result between 5% to 25% in the bone marrow aspirate or biopsy. Nonresponders (NR) had a pre- and 1 or more post-baseline BM assessment carried out, but results did not meet any response criteria. Participants who were not evaluable (NE) did not have at least 14 days of treatment and were not assessed. | Baseline up to 28 days after the last dose, up to approximately 3 years | 
| Number of Participants Achieving a Best Disease Response by Dose Cohort in Terms of Best Overall Response Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia | Complete Response (CR) response criteria included either a post-baseline bone marrow biopsy or aspiration % blasts <5%, absolute neutrophil count (ANC) >1×10^9/L and platelet count >100×10^9/L on the same date as the qualifying bone marrow assessment. CRp response included all CR criteria met except participant did not experience a platelet recovery. Participants must have experienced an ANC Recovery. CRi response included a qualifying bone marrow result, but did not experience an ANC recovery. Participants may or may not have experienced a platelet recovery and were not required to be transfusion independent. Partial remission (PR) response included a decrease of ≥50% in % blasts in the bone marrow aspirate or biopsy from baseline to a post-baseline result between 5% to 25% in the bone marrow aspirate or biopsy. Nonresponders (NR) had a pre- and 1 or more post-baseline bone marrow assessment carried out, but results did not meet any of the CR or PR or progressive disease criteria. | Baseline up to 28 days after the last dose, up to approximately 3 years | 
| Number of Participants With Hematologic Improvement Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia | Hematologic improvement is summarized in terms of Erythroid Response (HI-E), Platelet Response (HI-P), Neutrophil Response (HI-N), and Hematologic Improvement (HI). For post-treatment results, HI-E major responders had >2 g/dL increase in hemoglobin for at least 1 result after first treatment and transfusion independent; minor responders 1 to 2 g/dL increase in hemoglobin for at least 1 result post first treatment and a 50% decrease in red blood cell transfusion requirements. For HI-P, major responders had ≥30 × 10^9/L increase in platelet count and transfusion independent; minor responders had 50% or more increase in platelet count with a net increase between 10 to 30 × 10^9/L and 50% decrease in platelet transfusion requirements. For HI-N, major responders had an increase in absolute neutrophil count (ANC) of 100% or an absolute increase of more than 0.5 × 10^9/L (whichever is greater); minor responders had an increase in ANC of 100% but an absolute increase of <0.5 × 10^9/L. | Baseline up to 28 days after the last dose, up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RTK, kinase, inhibitor, tyrosine, acute, FLT3, AC220, pharmacokinetic, pharmacokinetics, PK, pharmacodynamic, pharmacodynamics, mutations, PD, receptor, class III, relapsed, refractory, t(8;21), q22;q22, AML1/ETO, t(16;16, p13;q22, CBFbeta/MYH11, inv(16), p13q22, 11q23, dysplasia, myeloid, myelomonocytic, monoblastic, monocytic, erythroid, erythroleukemia, megakaryoblastic, basophilic, panmyelosis, myelofibrosis