Dasatinib, Ifosfamide, Carboplatin, and Etoposide in Treating Young Patients With Metastatic or Recurrent Malignant Solid Tumors

Brain and Central Nervous System Tumors, Childhood Germ Cell Tumor, Extragonadal Germ Cell Tumor, Kidney Cancer, Liver Cancer, Lymphoma, Neuroblastoma, Ovarian Cancer, Sarcoma, Testicular Germ Cell Tumor, Unspecified Childhood Solid Tumor, Protocol Specific

previously treated childhood rhabdomyosarcoma, metastatic childhood soft tissue sarcoma, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, metastatic osteosarcoma, recurrent childhood rhabdomyosarcoma, recurrent childhood soft tissue sarcoma, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent osteosarcoma, unspecified childhood solid tumor, protocol specific, recurrent Wilms tumor and other childhood kidney tumors, recurrent neuroblastoma, stage 4S neuroblastoma, childhood extracranial germ cell tumor, childhood malignant ovarian germ cell tumor, childhood malignant testicular germ cell tumor, childhood teratoma, clear cell sarcoma of the kidney, childhood renal cell carcinoma, recurrent renal cell cancer, congenital mesoblastic nephroma, cystic nephroma, peripheral primitive neuroectodermal tumor of the kidney, rhabdoid tumor of the kidney, disseminated neuroblastoma, recurrent malignant testicular germ cell tumor, recurrent ovarian germ cell tumor, recurrent childhood liver cancer, stage IV childhood liver cancer, angioimmunoblastic T-cell lymphoma, stage IV childhood Hodgkin lymphoma, stage IV childhood large cell lymphoma, stage IV childhood lymphoblastic lymphoma, stage IV childhood small noncleaved cell lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, recurrent childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent/refractory childhood Hodgkin lymphoma, childhood diffuse large cell lymphoma, childhood grade III lymphomatoid granulomatosis, childhood immunoblastic large cell lymphoma, childhood nasal type extranodal NK/T-cell lymphoma, Burkitt lymphoma, recurrent childhood anaplastic large cell lymphoma, stage IV childhood anaplastic large cell lymphoma, childhood central nervous system choriocarcinoma, childhood central nervous system embryonal tumor, childhood central nervous system germ cell tumor, childhood central nervous system germinoma, childhood central nervous system mixed germ cell tumor, childhood central nervous system teratoma, childhood central nervous system yolk sac tumor, recurrent childhood central nervous system embryonal tumor, childhood choroid plexus tumor, childhood craniopharyngioma, childhood ependymoblastoma, childhood medulloepithelioma, childhood infratentorial ependymoma, childhood supratentorial ependymoma, childhood oligodendroglioma, childhood pineal parenchymal tumor, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood pineoblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, recurrent childhood visual pathway and hypothalamic glioma, recurrent uterine sarcoma, childhood high-grade cerebellar astrocytoma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebellar astrocytoma, childhood low-grade cerebral astrocytoma, childhood atypical teratoid/rhabdoid tumor, primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma, childhood extragonadal germ cell tumor, recurrent childhood malignant germ cell tumor, recurrent childhood brain stem glioma, recurrent childhood subependymal giant cell astrocytoma, recurrent childhood brain tumor, recurrent childhood spinal cord neoplasm

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs in chemotherapy, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving dasatinib together with ifosfamide, carboplatin, and etoposide may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of dasatinib when given together with ifosfamide, carboplatin, and etoposide and to see how well they work in treating young patients with metastatic or recurrent malignant solid tumors.

OBJECTIVES: Primary * To determine the maximum tolerated dose (MTD) of dasatinib when given immediately following ifosfamide, carboplatin, and etoposide phosphate (D-ICE) as a re-induction regimen in young patients with metastatic or recurrent malignant solid tumors. (Phase I) * To describe and define the toxicities of D-ICE in these patients. (Phase I) * To determine the safety and feasibility of prolonged administration of single-agent dasatinib following completion of 2-6 courses of D-ICE in these patients. (Phase I) * To estimate the overall survival, progression-free survival, and time to progression in patients treated with D-ICE at the MTD followed by single-agent dasatinib. (Phase II) * To estimate the response rate to two courses of D-ICE when given at the MTD in these patients. (Phase II) Secondary * To determine the phosphotyrosine state of SRC family kinases and related signaling pathways, including FAK, STAT3, VEGFR, AKT, EGFR, KIT, EPHA2, and PDGFR, in paraffin-embedded tumor samples as measured by immunohistochemistry prior to and during treatment with dasatinib. * To assess gene expression profiling in fresh frozen tissue samples as measured by microarray analysis (Affymetrix GeneChips) at baseline to identify molecular signatures that may predict response to dasatinib. * To correlate biomarkers and molecular signatures with dasatinib dosage, toxicity, and antitumor activity. * To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in peripheral blood mononuclear cell samples as a surrogate marker of response prior to treatment with dasatinib, at days 14-21 or when WBC ≥ 500/μL, during each treatment course, at the time of local control, and at the time of progression. OUTLINE: This is a multicenter, phase I, dose-escalation study of dasatinib followed by a phase II study. Patients enrolled in phase II are stratified according to disease. Patients receive D-ICE comprising oral dasatinib twice daily on days 5-21, ifosfamide IV over 1 hour and etoposide phosphate IV over 1 hour on days 1-5, and carboplatin IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo radiotherapy and/or surgery (consolidation therapy) after 2, 4, or 6 courses of D-ICE. After completion of consolidation therapy, patients receive oral dasatinib twice daily for up to 6 months in the absence of disease progression or unacceptable toxicity. Tumor tissue and peripheral blood mononuclear cell (PBMC) samples are collected periodically for correlative laboratory studies. PBMCs are analyzed by western blotting for total and phospho-SRC, phospho-FAK, and other relevant biomarkers. Tumor tissue samples are analyzed by IHC for total and phospho-SRC, phospho-FAK, phospho-STAT3, phospho-KIT, and phospho-PDGFR, EPHA2, and VEGF. Tumor tissue samples are also analyzed by microarray gene expression profiling to define a potential molecular signature or gene expression pattern that may predict response to dasatinib. After completion of study treatment, patients are followed periodically.

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