Dasatinib, Ifosfamide, Carboplatin, and Etoposide 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.

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