Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02680951
Recruitment Status : Withdrawn (Withdrawn due to lack of participants.)
First Posted : February 12, 2016
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
Melinda Pauly, Emory University

Brief Summary:
This study will examine the appropriate dose and side effects of dasatinib, when it is given with the standard of care chemotherapy for children and adolescents with Acute Myeloid Leukemia (AML).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Dasatinib Drug: Fludarabine Drug: Cytarabine Drug: Idarubicin Drug: Intrathecal (IT) cytarabine Phase 1

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia: A Phase I Study (AflacLL1401)
Actual Study Start Date : December 2015
Actual Primary Completion Date : December 15, 2017
Actual Study Completion Date : December 15, 2017


Arm Intervention/treatment
Experimental: Dose Level 1

Study participants #1 - #6 receive dose level 1 of dasatinib (60/mg/m2/day) in addition to the standard treatment, for up to 2 courses. Each treatment course is 29 days.

Treatment course 1 consists of:

  • Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5
  • Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5
  • Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5
  • Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines
  • Dasatinib orally, once daily on days 6-29

Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.

Drug: Dasatinib
Administered orally on a once daily schedule based on the dose level assigned to the patient at enrollment (60, 80, or 100mg/m2/day). Patients may adjust the time they take dasatinib as long as they take the drug approximately every 24 hours
Other Names:
  • Sprycel
  • BMS-354825

Drug: Fludarabine

30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the fludarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Fludara

Drug: Cytarabine

2000 mg/m2/dose intravenous infusion over 1 to 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the cytarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Names:
  • Depocyt
  • Cytosar-U

Drug: Idarubicin

8mg/m2/dose intravenous infusion over 15 minutes, once daily, on days 3 to 5, total 3 doses

Participants with body weight less than 12Kg, the idarubicin dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Idamycin

Drug: Intrathecal (IT) cytarabine

Given intrathecally to all participants on day 1 of course 1 and 2. Omit on day 1 of course 1 if participant received IT therapy within 7 days prior to study enrollment. Intrathecal chemotherapy may be given during the end of course 1 disease evaluation (spinal fluid and bone marrow aspiration) and may be repeated every 7 days with bone marrow evaluations per institutional preference.

Cytarabine dose defined by age:

  • 30 mg for patients age 1 - 1.99
  • 50 mg for patients age 2 - 2.99
  • 70 mg for patients ≥3 years of age

The participant may receive intrathecal triple therapy (ITT) if persistent blasts are present in the cerebral spinal fluid (CSF) based on the treating physician's clinical judgment.

Other Names:
  • Depocyt
  • Cytosar-U

Experimental: Dose Level 2

Study participants # 7 - # 12 receive dose level 2 of dasatinib (80/mg/m2/day) in addition to the standard treatment (up to 2 courses), if the participants receiving Dose Level 1 did not experience intolerable side effects. Each treatment course is 29 days.

Treatment course 1 consists of:

  • Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5
  • Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5
  • Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5
  • Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines
  • Dasatinib orally, once daily on days 6-29

Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.

Drug: Dasatinib
Administered orally on a once daily schedule based on the dose level assigned to the patient at enrollment (60, 80, or 100mg/m2/day). Patients may adjust the time they take dasatinib as long as they take the drug approximately every 24 hours
Other Names:
  • Sprycel
  • BMS-354825

Drug: Fludarabine

30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the fludarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Fludara

Drug: Cytarabine

2000 mg/m2/dose intravenous infusion over 1 to 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the cytarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Names:
  • Depocyt
  • Cytosar-U

Drug: Idarubicin

8mg/m2/dose intravenous infusion over 15 minutes, once daily, on days 3 to 5, total 3 doses

Participants with body weight less than 12Kg, the idarubicin dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Idamycin

Drug: Intrathecal (IT) cytarabine

Given intrathecally to all participants on day 1 of course 1 and 2. Omit on day 1 of course 1 if participant received IT therapy within 7 days prior to study enrollment. Intrathecal chemotherapy may be given during the end of course 1 disease evaluation (spinal fluid and bone marrow aspiration) and may be repeated every 7 days with bone marrow evaluations per institutional preference.

Cytarabine dose defined by age:

  • 30 mg for patients age 1 - 1.99
  • 50 mg for patients age 2 - 2.99
  • 70 mg for patients ≥3 years of age

The participant may receive intrathecal triple therapy (ITT) if persistent blasts are present in the cerebral spinal fluid (CSF) based on the treating physician's clinical judgment.

Other Names:
  • Depocyt
  • Cytosar-U

Experimental: Dose Level 3

Study participants # 13 - # 18 receive dose level 3 of dasatinib (100/mg/m2/day) in addition to the standard treatment (up to 2 courses), if the participants receiving Dose Level 2 did not experience intolerable side effects. Each treatment course is 29 days.

Treatment course 1 consists of:

  • Fludarabine at a dose of 30mg/m2, intravenously once daily on days 1-5
  • Cytarabine at a dose of 2000mg/m2, intravenously once daily on days 1-5
  • Idarubicin at a dose of 8mg/m2, intravenously once daily on days 3-5
  • Intrathecal cytarabine on day 1 according to standard age specific dosing guidelines
  • Dasatinib orally, once daily on days 6-29

Participants achieving a response of standard disease or better are eligible for course 2 consisting of dasatinib with fludarabine and cytarabine alone.

Drug: Dasatinib
Administered orally on a once daily schedule based on the dose level assigned to the patient at enrollment (60, 80, or 100mg/m2/day). Patients may adjust the time they take dasatinib as long as they take the drug approximately every 24 hours
Other Names:
  • Sprycel
  • BMS-354825

Drug: Fludarabine

30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the fludarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Fludara

Drug: Cytarabine

2000 mg/m2/dose intravenous infusion over 1 to 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 1 to 5, total 5 doses

Participants with body weight less than 12Kg, the cytarabine dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Names:
  • Depocyt
  • Cytosar-U

Drug: Idarubicin

8mg/m2/dose intravenous infusion over 15 minutes, once daily, on days 3 to 5, total 3 doses

Participants with body weight less than 12Kg, the idarubicin dose will be corrected as follows: [weight (Kg) x dose (per m2)] divided by 30

Other Name: Idamycin

Drug: Intrathecal (IT) cytarabine

Given intrathecally to all participants on day 1 of course 1 and 2. Omit on day 1 of course 1 if participant received IT therapy within 7 days prior to study enrollment. Intrathecal chemotherapy may be given during the end of course 1 disease evaluation (spinal fluid and bone marrow aspiration) and may be repeated every 7 days with bone marrow evaluations per institutional preference.

Cytarabine dose defined by age:

  • 30 mg for patients age 1 - 1.99
  • 50 mg for patients age 2 - 2.99
  • 70 mg for patients ≥3 years of age

The participant may receive intrathecal triple therapy (ITT) if persistent blasts are present in the cerebral spinal fluid (CSF) based on the treating physician's clinical judgment.

Other Names:
  • Depocyt
  • Cytosar-U




Primary Outcome Measures :
  1. Safety of Dasatinib assessed by the Number of Adverse Events [ Time Frame: Duration of Study (Up to 161 Days) ]
    The number of adverse events throughout the duration of the study will be collected to assess the safety of dasatinib.

  2. Number of Dose-Limiting Toxicities (DLT) [ Time Frame: Duration of Course 1 (Up to 42 Days) ]
    The number of dose limiting toxicities (DLT) as defined by grade 3 or higher non-hematologic adverse events persisting for great than 48 hours without resolution to a grade 2 or less, grade 2 pleural effusion that persists longer than 1 week, failure to recover an absolute neutrophil count (ANC) of greater than 500/µL, and platelet count of greater than 50,000/µL. Dose level toxicities will be assessed in the first course only.

  3. Maximum Tolerated Dose (MTD) [ Time Frame: Duration of Study (Up to 161 Days) ]
    The MTD will be the highest dose at which 1 or fewer of six patients experience dose-limiting toxicities (DLT).


Secondary Outcome Measures :
  1. Remission Status assessed by Bone Marrow Aspiration/Biopsy [ Time Frame: Between Day 29 and Day 43 ]
    A single bone marrow aspiration/biopsy will be performed to assess remission status between day 29 and 43. The exact time point of the bone marrow aspiration/biopsy is dependent on blood count recovery (absolute neutrophil count of greater than 500). Day 43 is the last day remission status must be assessed.

  2. Effect of Dasatinib on c-KIT Expression assessed by Phosphorylation of Stat3 [ Time Frame: Baseline, End of course 1 (Up to 49 days) ]
    The effect of dasatinib on c-KIT expression will be measured by phosphorylation of Stat3 in a core binding factor acute myeloid leukemia (CBF AML) cell line treated with patient plasma.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed relapsed or refractory Acute Myeloid Leukemia (AML) and meet the following criteria: Relapsed disease is defined as AML in 1st or greater marrow relapse; Refractory disease is defined as AML which failed to go into remission after 1st or greater relapse, OR AML which failed to go into remission after two or more induction attempts from original diagnosis
  • ≥ 5% blasts by morphology in the bone marrow or molecular evidence of at least 0.1% leukemic blasts in the bone marrow
  • Definitive evidence of t(8;21) or inv(16) by a CLIA approved cytogenetics laboratory from initial diagnosis
  • CNS or other sites of extramedullary disease. No cranial irradiation is allowed during the protocol therapy
  • Lansky ≥ 50 for patients ≤ 16 years old; Karnofsky ≥ 50 for patients > 16 years old
  • Have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiation therapy prior to entering this study
  • Have adequate renal and hepatic functions
  • A shortening fraction greater than or equal to 27% by echocardiogram, OR ejection fraction greater than or equal to 50% by radionuclide angiogram (MUGA)
  • Must not have any evidence of dyspnea at rest, exercise intolerance, and must have a pulse oximetry > 94% at sea level
  • Patients with a seizure disorder may be enrolled if well controlled on anticonvulsants at a dose that has been stable for at least 14 days
  • Female participants of childbearing potential must have a negative urine or serum pregnancy test confirmed within 24 hours prior to enrollment
  • Female participants with infants must agree not to breastfeed their infants while on this study
  • Male and female participants 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:

  • Known allergy to any of the drugs used in the study
  • Systemic fungal, bacterial, viral or other infection of which they exhibit ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment
  • Any clinically significant cardiovascular disease including: myocardial infarction or ventricular tachyarrhythmia within 6 months, prolonged QTc > 480 msec by the Fridericia correction, major conduction abnormality, such as 2nd or 3rd degree heart block or symptomatic bundle branch block, unless a cardiac pacemaker is present
  • Plans to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period
  • Refractory to red blood cell or platelet transfusions
  • Receiving anti-coagulation therapy
  • A need to administer drugs that inhibit platelet function, such as aspirin or clopidogrel
  • Receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's Wort
  • Significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results
  • Individuals with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome)

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): NCT02680951


Sponsors and Collaborators
Emory University
Investigators
Layout table for investigator information
Principal Investigator: Melinda Pauly, MD Emory University
Layout table for additonal information
Responsible Party: Melinda Pauly, MD, Emory University
ClinicalTrials.gov Identifier: NCT02680951    
Other Study ID Numbers: IRB00078620
First Posted: February 12, 2016    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: April 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Melinda Pauly, Emory University:
Pediatric
Adolescent
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Dasatinib
Idarubicin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors