INCLUSION CRITERIA:
Age: Patients must be greater than 12 months and less than or equal to 21 years of age at the time of study entry.
Diagnosis: Patients must have had histologic verification of solid tumor malignancy at either original diagnosis or relapse, or have imatinib resistant Ph plus acute lymphoblastic or chronic myelogenous leukemia. Patients with tumors of the central nervous system are not eligible.
Imatinib resistance in Ph plus CML is defined as any of the following:
Increasing WBC or platelet count while on imatinib therapy.
Lack of any cytogenetic response after an adequate duration of imatinib therapy as defined below:
a) Failure to achieve a complete hematological response after completion of 3 months of imatinib
OR
b) Failure to achieve a partial or complete cytogenetic response (i.e. less than or equal to 35% Ph plus) after 6 months of imatinib.
Appearance of accelerated or blastic feature while on imatinib therapy.
Reappearance of Ph plus clones after an initial complete cytogenetic response to imatinib.
An increase in Ph plus cells of greater than 30% while on imatinib therapy in peripheral blood or bone marrow cytogenetics.
Imatinib intolerance as defined by development of adverse effects requiring discontinuation of imatinib therapy.
Imatinib resistance in Ph plus ALL is defined as a M3 bone marrow in a patient who has previously received an Imatinib containing treatment regimen.
Disease Status:
Patients with a solid tumor must have either measurable or evaluable disease.
Patients with leukemia must have measurable disease. For patients with CML, hematologic, cytogenetic, and molecular studies will determine measurable disease. For patients with ALL, bone marrow blast percentage will determine measurable disease. Patients with CNS-positive leukemia are eligible.
Therapeutic Options: Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
Performance Level: Karnofsky greater than or equal to 50% for patients greater than 10 years of age, and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age.
Prior Therapy:
Patients with solid tumors must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patients with leukemias must have recovered from the non-hematologic toxic effects of all prior therapy and must not be known to be refractory to red cell or platelet transfusion before entry
onto this trial.
a. Myelosuppressive Chemotherapy:
Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks or nitrosourea within 6 weeks of entry onto this study.
For patients with Ph plus leukemia, cytoreduction can be initiated with hydroxyurea (suggested hydroxyurea regimen: 20-30 mg/kg/day; escalate as needed to 80-100 mg/kg/day) and can be
continued for up to 24 hours prior to start of Dasatinib. Patients with CNS-positive leukemia may have received IT therapy prior to enrollment.
b. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta® (Registered Trademark)) administration.
c. 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.
d. XRT: greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 3 months must have elapsed if prior TBI, or craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation.
e. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and greater than or equal to 3 months must have elapsed since SCT.
Organ Function Requirements.
Adequate Bone Marrow Function Defined As:
a. For patients with solid tumors:
Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microliter.
Platelet count greater than or equal to 100,000/microliter (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).
Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions).
b. Patients with known bone marrow metastatic disease will be eligible for study but not evaluable for hematologic toxicity. These patients must not be known to be refractory to red cell or platelet transfusion. At least 2 of every cohort of 3 patients must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity.
c. For patients with leukemia:
Platelet count greater than or equal to 20,000/microliter (may receive platelet transfusions).
Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions).
Adequate Renal Function Defined As:
Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m(2), or
A serum creatinine based on age/gender as follows:
1 to less than 2 years equals a Maximum Serum Creatinine (mg/dL) of 0.6 for male and 0.6 for female.
2 to less than 6 years equal s a Maximum Serum Creatinine (mg/dL) of 0.8 for male and 0.8 for female.
6 to less than 10 years equal a Maximum Serum Creatinine (mg/dL) of 1 for male and 1 for female.
10 to less than 13 years equal a Maximum Serum Creatinine (mg/dL) of 1.2 for male and 1.2 for female.
13 to less than 16 years equal a Maximum Serum Creatine (mg/dL) of 1.5 for male and 1.4 for female.
Greater than or equal to 16 years equal a Maximum Serum Creatinine (mg/dL) of 1.7 for male and 1.4 for female.
The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
Adequate Liver Function Defined As:
Bilirubin (sum of conjugated plus unconjugated) less than or equal to 1.5 times upper limit normal (ULN) for age, and
SGPT (ALT) less than or equal to 110. For the purpose of this study, the ULN for SGPT is 45 U/L.
Serum albumin greater than or equal to 2 g/dL.
Adequate Cardiac Function Defined As:
Normal 12 lead EKG with corrected QTc less than 450 msec, and either
Shortening fraction greater than the institutional lower limit of normal
or
Ejection fraction greater than the institutional lower limit of normal.
Adequate Pulmonary Function Defined As:
No evidence of dyspnea at rest, no exercise intolerance, and a pulse
oximetry greater than 94% if there is clinical indication for determination.
Informed Consent: All patients and/or their parents or legal guardians must sign written informed consent. Assent, when appropriate, will be obtained according institutional guidelines.
EXCLUSION CRITERIA:
Pregnancy or Breast-Feeding
Pregnant or breast-feeding women will not be entered on this study due to risks fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests be obtained in girls who are post menarchal. Males or females of reproductive potential may not participate unless they have agreed to use effective contraceptive method.
Concomitant Medications
Growth factor(s): Growth factors that support the number or function platelets or white cells must not have been administered within the past 7 days. Pegfligrastim (Neulasta® (Registered Trademark)) must not have been administered within the past 14 days.
Investigational Agents: Patients who are currently receiving another investigational drug.
Anti-cancer Agents: Patients who are currently receiving other anticancer agents. Patients with CNS-positive leukemia may receive ITT therapy. Patients receiving hydroxyurea for Ph plus leukemia (suggested hydroxyurea regimen: 20-30 mg/kg/day; escalate as needed to 80-100 mg/kg/day) may enroll on the trial, provided that the hydroxyurea is discontinued at least 24 hours prior to initiation of Dasatinib.
Enzyme inducing anticonvulsants: phenytoin, phenobarbital, felbamate, primdone, oxcarbazepine and/or carbamazepine.
Anti-thrombotic and anti-platelet agents: warfarin (coumadin ® (Registered Trademark)), heparin, low molecular weight heparin, aspirin, and/or ibuprofen, or other NSAIDs.
The following CYP3A4 inhibitors: itraconazole, ketoconazole, and voriconazole.
Infection: Patients who have an uncontrolled infection.
Patients who are unable to swallow oral or liquid medication.
HIV plus patients whose HAART regimen may interact with Dasatinib.
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009