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

This study has been completed.
Sponsor:
Collaborator:
Ambit Biosciences Corporation
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:
NCT01411267
First received: August 1, 2011
Last updated: May 17, 2013
Last verified: May 2013
  Purpose

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 Intervention Phase
Lymphoblastic Leukemia, Acute, Childhood
Myelogenous Leukemia, Acute, Childhood
Drug: AC220
Drug: Cytarabine
Drug: Etoposide
Drug: Methotrexate
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of AC220 for Children With Relapsed or Refractory ALL or AML

Resource links provided by NLM:


Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:
  • The dose of AC220 that can be given safely with etoposide and cytarabine. [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    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:
  • The response rate after treatment. [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
  • Composite pharmacokinetics of AC220. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Measure the levels of AC220 in the blood during treatment.

  • FLT-3 mutation in cancer cells before and after treatment. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Inhibition of FLT3 phosphorylation [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Enrollment: 24
Study Start Date: August 2011
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
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
    • AMETHOPTERIN
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.

  Eligibility

Ages Eligible for Study:   1 Month to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01411267

  Show 28 Study Locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Ambit Biosciences Corporation
Investigators
Study Chair: Todd Cooper, MD Children's Healthcare of Atlanta, Emory University
  More Information

Additional Information:
No publications provided

Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01411267     History of Changes
Other Study ID Numbers: T2009-004
Study First Received: August 1, 2011
Last Updated: May 17, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Relapse
Lymphoblastic
Leukemia
AC220
Refractory
Myelogenous
Acute
Childhood
Pediatric
ALL
AML

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

ClinicalTrials.gov processed this record on September 18, 2014