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

NCT02680951 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: IRB00078620
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Acute Myeloid Leukemia

Keywords

Pediatric; Adolescent

Outcome Measures

Primary Outcomes (3)

• Safety of Dasatinib assessed by the Number of Adverse Events

  The number of adverse events throughout the duration of the study will be collected to assess the safety of dasatinib.

  Duration of Study (Up to 161 Days)

• Number of Dose-Limiting Toxicities (DLT)

  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.

  Duration of Course 1 (Up to 42 Days)

• Maximum Tolerated Dose (MTD)

  The MTD will be the highest dose at which 1 or fewer of six patients experience dose-limiting toxicities (DLT).

  Duration of Study (Up to 161 Days)

Secondary Outcomes (2)

• Remission Status assessed by Bone Marrow Aspiration/Biopsy

  Between Day 29 and Day 43

• Effect of Dasatinib on c-KIT Expression assessed by Phosphorylation of Stat3

  Baseline, End of course 1 (Up to 49 days)

Study Arms (3)

Dose Level 1

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: Intrathecal (IT) cytarabine

Dose Level 2

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: Intrathecal (IT) cytarabine

Dose Level 3

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cytarabine; Drug: Idarubicin; Drug: Intrathecal (IT) cytarabine

Interventions

Dasatinib DRUG

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

Also known as: Sprycel, BMS-354825

Dose Level 1; Dose Level 2; Dose Level 3

Fludarabine DRUG

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

Also known as: Fludara

Dose Level 1; Dose Level 2; Dose Level 3

Cytarabine DRUG

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

Also known as: Depocyt, Cytosar-U

Dose Level 1; Dose Level 2; Dose Level 3

Idarubicin DRUG

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

Also known as: Idamycin

Dose Level 1; Dose Level 2; Dose Level 3

Intrathecal (IT) cytarabine DRUG

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.

Also known as: Depocyt, Cytosar-U

Dose Level 1; Dose Level 2; Dose Level 3

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Emory University: lead

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Dasatinib; fludarabine; fludarabine phosphate; Cytarabine; Idarubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Cytidine; Pyrimidine Nucleosides; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Melinda Pauly, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: February 9, 2016
• First Posted: February 12, 2016
• Study Start: December 1, 2015
• Primary Completion: December 15, 2017
• Study Completion: December 15, 2017
• Last Updated: April 19, 2018

Record last verified: 2018-04