Clinical trial NCT00462761: A Phase I Study of AC220 in Patients With Relapsed/Refractory Acute Myeloid Leukemia Regardless of FLT3 Status
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Leukemia
Myelodysplastic Syndrome
AML
MDS
Keywords: 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
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2007-04-19
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Treatment Related Adverse Events Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia
timeFrame: Baseline up to 30 days post last dose
measure: 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
timeFrame: Baseline up to 30 days post last dose
Secondary outcomes:
measure: 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
timeFrame: Baseline up to 28 days after the last dose, up to approximately 3 years
measure: 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
timeFrame: Baseline up to 28 days after the last dose, up to approximately 3 years
measure: 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
timeFrame: Baseline up to 28 days after the last dose, up to approximately 3 years
measure: Number of Participants With Hematologic Improvement Following Oral Administration of Quizartinib in Participants With Relapsed or Refractory Acute Myeloid Leukemia
timeFrame: Baseline up to 28 days after the last dose, up to approximately 3 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: T'Bilisi
country: Georgia
facility: Chemotherapy and Immunotherapy Clinic
city: T'bilisi
country: Georgia
facility: Hematology and Chemotherapy Clinic
Study officials:
affiliation: Daiichi Sankyo
name: Clinical Director
role: STUDY_DIRECTOR
References:
citation: 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.