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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

Phase 1
18 Years
Not Enrolling
Acute Myeloid Leukemia, Leukemia, Myelodysplastic Syndrome, AML, MDS

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Trial Information

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

This is a multi-center clinical study conducted in the USA and possibly two international
sites. It is open-label, dose escalation study 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 receive AC220 until dose
limiting toxicity is noted (DLT). At that point cohorts will expand to 6 patients until MTD
is determined. Patients not experiencing DLT or significant disease progression at Day 15
may continue receiving AC220 at the discretion of the Investigator and Sponsor. FLT3
positive and negative patients are allowed to participate.

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability

Outcome Description:

The primary objectives of this study are to:•Determine the safety and tolerability, including dose limiting toxicity (DLT), of oral AC220 when administered daily to patients with relapsed or treatment-refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Guy Gammon, MB BS, MRCP

Investigator Role:

Study Director

Investigator Affiliation:

Interim Chief Medical Officer, Ambit Biosciences Corporation


United States: Food and Drug Administration

Study ID:




Start Date:

January 2007

Completion Date:

December 2009

Related Keywords:

  • Acute Myeloid Leukemia
  • Leukemia
  • Myelodysplastic Syndrome
  • AML
  • MDS
  • 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
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



MD Anderson Cancer Center Houston, Texas  77030-4096
University of Nebraska Medical Center Omaha, Nebraska  68198-3330
University of Alabama at Birmingham Birmingham, Alabama  35294-3300