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

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.

Eligibility Criteria:
DISEASE CHARACTERISTICS:

* Histologically confirmed malignant solid tumor that did not respond to or relapsed after standard first-line chemotherapy or other antineoplastic therapy (if the standard therapy for the tumor is generally recognized to be beneficial)

  * Must have been initially diagnosed with malignancy prior to 25 years of age
  * Radiographic, nuclear image, or biopsy confirmation of disease within the past 4 weeks
* Meets one of the following criteria:

  * Phase I: Relapsed/refractory malignant solid tumor (excluding CNS tumors)

    * Patients with recurrent or metastatic disease that was completely resected just prior to study entry are eligible
  * Phase II: Patients are stratified according to one of the following diagnoses:

    * Stratum A: Relapsed sarcoma (rhabdomyosarcoma, osteosarcoma, or Ewing sarcoma)
    * Stratum B: Other relapsed solid tumors, including any of the following:

      * Other soft tissue sarcomas
      * Kidney tumors
      * Lymphoma
      * CNS tumors\*
      * Other solid tumors (neuroblastoma, gonadal and germ cell tumors, liver tumors, or miscellaneous tumors)
    * Stratum C: Newly diagnosed, poor-risk metastatic sarcoma consisting of unresectable pulmonary metastases (≥ 6 nodules) and/or disease involving multiple bones or other organs NOTE: \*Patients with recurrent primary CNS tumors are eligible for the phase II portion of this study provided there are no significant intratumoral bleeding toxicities seen in either COG pediatric phase I studies of dasatinib or the phase I portion of this study
* Radiographically measurable disease (Phase II)

  * Measurable disease is not required for patients who are enrolled in the phase I portion of this study
* No bone marrow involvement (Phase I)

  * Patients with bone marrow involvement are eligible for the phase II portion of this study provided they are not known to be refractory to red cell or platelet transfusions

PATIENT CHARACTERISTICS:

* Lansky performance status (PS) 50-100% (patients 1-16 years of age) or Karnofsky PS 50-100% (patients \> 16 years of age)
* Life expectancy ≥ 8 weeks
* ANC \> 1,000/μL
* Platelet count \> 75,000/μL
* Creatinine clearance or GFR ≥ 70 mL/min OR creatinine \< 1.5 times upper limit of normal (ULN)
* Bilirubin \< 1.5 times ULN for age
* SGOT or SGPT \< 2.5 times ULN for age (\< 5 times ULN if liver involvement by tumor)
* Ejection fraction normal by MUGA OR shortening fraction \> 28%
* No evidence of cardiac arrhythmias requiring therapy
* Corrected QTc interval \< 450 msecs
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Able to comply with the safety monitoring requirements of this study
* No uncontrolled infection
* No swallowing dysfunction that would preclude oral medication intake

  * Gastric or jejunal tube allowed provided it is functioning
* No history of significant bleeding disorder unrelated to cancer, including the following:

  * Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
  * Acquired bleeding disorder diagnosed within the past year (e.g., acquired anti-factor VIII antibodies)
  * Ongoing or recent (within the past 3 months) significant gastrointestinal bleeding

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Recovered from all prior therapy
* At least 7 days since prior and no concurrent drugs known to cause Torsades de Pointes, including the following:

  * Procainamide or disopyramide
  * Amiodarone, sotalol, ibutilide, or dofetilide
  * Erythromycin or clarithromycin
  * Chlorpromazine, haloperidol, mesoridazine, or thioridazine
  * Bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, or lidoflazine
* At least 3 weeks since prior chemotherapy (6 weeks for nitrosourea-containing therapy)
* At least 3 months since prior ifosfamide, carboplatin, and/or etoposide phosphate in the exact combination and dosage as administered in this study
* More than 7 days since prior filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-11
* More than 14 days since prior pegfilgrastim
* More than 30 days since prior epoetin alfa
* No prior cranial-spinal irradiation at doses \> 2,400 cGy
* No prior radiotherapy, including total-body irradiation, to \> 50% of the bone marrow space
* No other concurrent investigational drugs or anticancer agents
* No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, phenobarbital, felbamate, primdone, oxcarbazepine, or carbamazepine)
* No concurrent anti-thrombotic or anti-platelet agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin, ibuprofen, or other NSAIDs)
* No concurrent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, or voriconazole)
* No concurrent highly active antiretroviral therapy for HIV-positive patients
* No concurrent St. John's wort
* No IV bisphosphonates during the first 8 weeks of dasatinib therapy