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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Leukemia; AML; Myelodysplastic Syndrome; MDS
• Intervention / Treatment: Drug: AC220

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 1

Contacts and Locations

Study Locations

• Georgia
  • T'Bilisi, Georgia
    • Chemotherapy and Immunotherapy Clinic
  • T'bilisi, Georgia
    • Hematology and Chemotherapy Clinic
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females age ≥ 18 years;

2. 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:

   1. Refractory to at least 1 cycle of induction chemotherapy, or
   2. Relapsed after at least 1 cycle of induction chemotherapy, or
   3. Patient is not, according to the clinical judgment of the Principal Investigator, a candidate for induction chemotherapy due to age, comorbidity, or other factors;
3. 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;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3;
5. 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;
6. Persistent chronic clinically significant toxicities from prior chemotherapy or surgery must be less than Grade 2;
7. Serum creatinine ≤ 2.0 mg/dL;
8. Total serum bilirubin ≤ 1.5 × ULN unless considered due to Gilbert's syndrome or leukemic organ involvement;
9. Serum AST or ALT ≤ 3.0 × ULN unless considered due to leukemic organ involvement;
10. Females of childbearing potential must have a negative pregnancy test (urine β-hCG);
11. Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study;
12. Written informed consent must be provided.

Exclusion Criteria:

1. Histologic diagnosis of acute promyelocytic leukemia;
2. Clinically active central nervous system leukemia;
3. 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);
4. Bone marrow transplant within 2 months prior to study;
5. Active, uncontrolled infection;
6. Major surgery within 4 weeks prior to study;
7. Radiation therapy within 4 weeks prior to, or concurrent with, study;
8. Human immunodeficiency virus positivity;
9. Active hepatitis B or C or other active liver disease;
10. Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential;
11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AC220; Determine safety, tolerability and pharmacokinetic (PK) parameters of AC220	Drug: AC220; 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.; Other Names: Quizartinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: April 17, 2007
• First Submitted That Met QC Criteria: April 17, 2007
• First Posted (Estimate): April 19, 2007

Study Record Updates

• Last Update Posted (Actual): May 11, 2020
• Last Update Submitted That Met QC Criteria: April 23, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: acute; pharmacokinetics; PK; pharmacokinetic; pharmacodynamics; relapsed; refractory; myelofibrosis; inhibitor; pharmacodynamic; tyrosine; PD; kinase; dysplasia; mutations; FLT3; myeloid; receptor; RTK; AC220; class III; t(8;21); inv(16); 11q23; monocytic; q22;q22; AML1/ETO; t(16;16; p13;q22; CBFbeta/MYH11; p13q22; myelomonocytic; monoblastic; erythroid; erythroleukemia; megakaryoblastic; basophilic; panmyelosis
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: CP0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR