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A Phase I Study of AC220 for Children With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

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ClinicalTrials.gov Identifier: NCT01411267
Recruitment Status : Completed
First Posted : August 8, 2011
Last Update Posted : May 21, 2013
Ambit Biosciences Corporation
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

Brief Summary:
This is a phase I study of the investigational drug AC220 combined with cytarabine and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).

Condition or disease Intervention/treatment Phase
Lymphoblastic Leukemia, Acute, Childhood Myelogenous Leukemia, Acute, Childhood Drug: AC220 Drug: Cytarabine Drug: Etoposide Drug: Methotrexate Phase 1

Detailed Description:

This is a study for patients with relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Some people diagnosed with leukemia have changes in a receptor located on the surface of white blood cells called FLT3. This is known as a FLT3 mutation. FLT3 plays an important role in the way cells grow and divide. In normal cells, the FLT3 receptor is switched off most of the time and only switches on when it gets a chemical signal from outside. But cells with the FLT3 mutation have the grow signal permanently switched on. This means leukemia cells with the FLT3 mutation are growing and dividing all the time. Doctors have found that people with leukemia cells that carry FLT3 mutations are less likely to go into remission with chemotherapy and have a higher risk of the leukemia coming back after treatment.

This is a study of an investigational drug called AC220. AC220 is considered investigational because it has not been approved in the United States by the Food and Drug Administration (FDA). AC220 is a drug which is able to "turn off" the FLT3 grow signal. AC220 will be given with cytarabine and etoposide to treat the relapsed leukemia. This is a phase I study, which means that the study is being done to find the highest dose of AC220 that can be given safely with the drugs cytarabine and etoposide to children and young adults.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of AC220 for Children With Relapsed or Refractory ALL or AML
Study Start Date : August 2011
Primary Completion Date : April 2013
Study Completion Date : May 2013

Intervention Details:
    Drug: AC220
    Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.
    Drug: Cytarabine

    1000 mg/m2/day IV given every 12 hours on days 1 through 5.

    IT cytarabine given intrathecally to patients with AML on day "0" of course 1 and 2. Dose defined by age

    • 30 mg for patients age 1-1.99 years of age
    • 50 mg for patients age 2-2.99 years of age
    • 70 mg for patients >3 years of age
    Other Names:
    • Cytosine Arabinoside
    • Ara-C
    • Cytosar®
    Drug: Etoposide
    150 mg/m2/day IV on days 1 through 5.
    Other Names:
    • VePesid
    • Etopophos
    • VP-16
    Drug: Methotrexate

    IT methotrexate given intrathecally to patients with ALL on day "0" of course 1 and 2. Dose defined by age

    • 8 mg for patients age 1-1.99
    • 10 mg for patients age 2-2.99
    • 12 mg for patients 3-8.99 years of age
    • 15 mg for patients >9 years of age
    Other Names:
    • MTX

Primary Outcome Measures :
  1. The dose of AC220 that can be given safely with etoposide and cytarabine. [ Time Frame: 6 weeks ]
    The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.

Secondary Outcome Measures :
  1. The response rate after treatment. [ Time Frame: 10 weeks ]
  2. Composite pharmacokinetics of AC220. [ Time Frame: 3 years ]
    Measure the levels of AC220 in the blood during treatment.

  3. FLT-3 mutation in cancer cells before and after treatment. [ Time Frame: 3 years ]
  4. Inhibition of FLT3 phosphorylation [ Time Frame: 3 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must be greater than 1 month and ≤ 21 years of age at study entry.
  • Patients must have a diagnosis of relapsed/refractory AML, ALL or acute leukemia of ambiguous lineage and meet the following criteria:

    1. Patients with AML or leukemia with ambiguous lineage must have greater than or equal to 5% blasts in the bone marrow.
    2. Patients with ALL must have an M3 marrow (marrow blasts >25%).
    3. Patients with ALL must have MLL gene rearrangement or hyperdiploid >50 chromosomes.
    4. Patients with treatment related AML (t-AML) are eligible, provided they meet all other eligibility criteria.
  • Karnofsky > 50% for patients >16 years of age and Lansky >50% for patients ≤16 years of age.
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    • Myelosuppressive chemotherapy:

      • Patients with ALL who relapse during standard maintenance therapy are eligible at time of relapse.
      • For patients with ALL and AML who relapse while they are receiving cytotoxic therapy, at least 14 days must have elapsed since the completion of cytotoxic therapy.
      • Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of AC220.
      • Patients who have received other FLT3 inhibitors (ex. lestaurtinib, sorafenib) are eligible for this study.
    • Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor.
    • Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    • XRT: 2 wks must have elapsed since local palliative XRT for CNS chloromas; No washout period is necessary for other chloromas; at least 3 months must have elapsed if prior TBI, craniospinal XRT.
    • Hematopoetic Stem Cell Transplant: At least 90 days must have elapsed since hematopoietic stem cell transplant (HSCT) and patients must not have active GVHD.
  • Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

    • Patients must have a calculated creatinine clearance or radioisotope GFR ≥70mL/min/1.73m2 or a normal serum creatinine based on age/gender.
    • Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin.
    • Alanine transaminase (ALT) <5 × ULN (unless related to leukemic involvement).
  • Patient must have a shortening fraction of ≥ 27% by echocardiogram, OR an ejection fraction of ≥ 50% by radionuclide angiogram.
  • Reproductive Function

    • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
    • Female patients with infants must agree not to breastfeed their infants while on this study.
    • Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

  • Patients will be excluded if they have CNS 3 disease.
  • Patients will be excluded if they have uncontrolled or significant cardiovascular disease, including:

    • A myocardial infarction within 12 months.
    • Uncontrolled angina within 6 months.
    • Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Sponsor's Medical Monitor prior to patient's entry into the study.
    • Prolonged QTcF interval on pre-entry ECG (≥450 ms).
    • Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker).
    • Heart rate < 50/minute on pre-entry ECG.
    • Uncontrolled hypertension.
    • Complete left bundle branch block.
    • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or TdP.
  • Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.
  • Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
  • Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  • Patients who are concurrently receiving CYP3A4 and 5 inhibitors and inducers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01411267

  Hide Study Locations
United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States
United States, California
City of Hope
Duarte, California, United States, 91010
Miller Children's Hospital
Long Beach, California, United States
Childrens Hospital Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital Central California
Madera, California, United States, 93636
Oakland Children's Hospital
Oakland, California, United States
Stanford University Medical Center
Palo Alto, California, United States, 94304-1812
UCSF School of Medicine
San Francisco, California, United States, 94143-0106
United States, Colorado
The Children's Hospital, University of Colorado
Aurora, Colorado, United States, 80045
United States, Florida
University of Miami Cancer Center
Miami, Florida, United States, 33136
United States, Georgia
Children's Healthcare of Atlanta, Emory University
Atlanta, Georgia, United States
United States, Illinois
Children's Memorial
Chicago, Illinois, United States
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States
United States, Massachusetts
Dana Farber
Boston, Massachusetts, United States
United States, Michigan
C.S. Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109-0914
United States, Minnesota
Childrens Hospital & Clinics of Minnesota
Minneapolis, Minnesota, United States, 55404-4597
University of Minnesota Children's Hospital
Minneapolis, Minnesota, United States
United States, Missouri
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, United States, 64108
United States, New York
New York University Medical Center
New York, New York, United States, 10016
Children's Hospital New York-Presbyterian
New York, New York, United States, 10032
United States, North Carolina
Levine Children's Hospital at Carolinas Medical Center
Charlotte, North Carolina, United States, 28203
United States, Ohio
Nationwide Childrens Hospital
Columbus, Ohio, United States
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
St. Jude
Memphis, Tennessee, United States, 38105-3678
Vanderbilt Children's Hospital
Nashville, Tennessee, United States
United States, Texas
Cook Children's Medical Center
Forth Worth, Texas, United States, 76104
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Ambit Biosciences Corporation
Study Chair: Todd Cooper, MD Children's Healthcare of Atlanta, Emory University

Additional Information:
Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01411267     History of Changes
Other Study ID Numbers: T2009-004
First Posted: August 8, 2011    Key Record Dates
Last Update Posted: May 21, 2013
Last Verified: May 2013

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Acute Disease
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors