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Dasatinib With Ifosfamide, Carboplatin, Etoposide: A Pediatric Phase I/II Trial


Phase 1/Phase 2
1 Year
25 Years
Open (Enrolling)
Both
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

Thank you

Trial Information

Dasatinib With Ifosfamide, Carboplatin, Etoposide: A Pediatric Phase I/II Trial


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of dasatinib (Phase I)

Safety Issue:

Yes

Principal Investigator

Judith K. Sato, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute

Authority:

United States: Food and Drug Administration

Study ID:

07053

NCT ID:

NCT00788125

Start Date:

September 2008

Completion Date:

Related Keywords:

  • 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
  • primary central nervous system non-Hodgkin 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 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
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Liver Neoplasms
  • Lymphoma
  • Nervous System Neoplasms
  • Neuroblastoma
  • Ovarian Neoplasms
  • Central Nervous System Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Neuroectodermal Tumors, Primitive
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma

Name

Location

City of Hope Comprehensive Cancer CenterDuarte, California  91010