Clinical Trials

OBJECTIVES:

       -  Collect biological specimens, including associated demographic and clinical data, from patients with Ewing sarcoma.

       -  Provide a repository for long-term storage of Ewing sarcoma-related biological materials.

       -  Make collected specimens available to qualified researchers to understand the biology of Ewing sarcoma and correlate these results with demographic and clinical data.

     OUTLINE: This is a multicenter study.

     Patients undergo collection of tumor specimens, bone marrow, and peripheral blood at diagnosis. Associated demographic and clinical data are collected and archived.

     Patients who are not enrolled on a therapeutic clinical trial are followed annually.

     PROJECTED ACCRUAL: Not specified.

PRIMARY OBJECTIVES:

     l. To determine the feasibility of administering bevacizumab in combination with intravenous vinorelbine and cyclophosphamide (VC) in patients with recurrent rhabdomyosarcoma (RMS).

     II. To determine the feasibility of administering temsirolimus in combination with VC in patients with recurrent RMS.

     III. To estimate the event-free survival (EFS) of patients with recurrent/refractory RMS treated with bevacizumab and VC and compare with the EFS of those treated with temsirolimus and VC.

     SECONDARY OBJECTIVES:

     I. To estimate the initial (2 cycle) response rate of patients with recurrent/refractory RMS treated with bevacizumab and VC and compare with the response rate of those treated with temsirolimus and VC, and to also compare the best response rate on each regimen of protocol therapy.

     II. To evaluate surrogate biological markers in patients with recurrent RMS and to estimate differences in these markers following treatment with bevacizumab and temsirolimus.

     OUTLINE: This is a multicenter study. Patients are stratified according to histologic sub type at initial diagnosis. Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive vinorelbine tartrate intravenously (IV) over 6-10 minutes on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1.

     ARM II: Patients receive vinorelbine tartrate and cyclophosphamide as in arm I. Patients also receive temsirolimus IV over 30-60 minutes on days 1, 8, and 15.

     In both arms, treatment repeats every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity. Blood and tissue samples may be collected for correlative studies.

     After completion of study treatment, patients are followed up annually for 5 years.

PRIMARY OBJECTIVES: l. To test the effect of the combination of vincristine, cyclophosphamide, and topotecan (VTC) added to the standard 5-drug chemotherapy interval-compressed backbone on event-free survival (EFS) and overall survival of children and young adults with Ewing sarcoma. SECONDARY OBJECTIVES: I. To evaluate initial volumetric tumor size as a prognostic factor for EFS in patients with localized Ewing tumors. II. To evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors. III. To continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study. IV. To evaluate imaging response by FDG-positron emission tomography (PET) as a prognostic factor for EFS. V. To evaluate the effects of the type of local therapy on EFS and overall survival. VI. To evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors. VII. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications. OUTLINE: This is a multicenter study. Patients are stratified according to age (≤ 17 years vs ≥ 18 years) and primary tumor site (pelvic vs non-pelvic vs extra-osseous). Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate on day 1 in weeks 1, 2, 7, 8, 9,10,13,14, 17,18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. ARM II: INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9,10,11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients with responsive or stable disease undergo may undergo surgery alone in week 13 if lesion can be complete resected with negative margins and with reasonable functional result. Patients with unresectable lesions or inadequate margins after surgery receive radiotherapy during weeks 1-7. Patients with bulky lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results may undergo radiotherapy alone in weeks 1-7 of consolidation therapy, and surgery should be performed after completion of consolidation chemotherapy. Patients with microscopic residual disease after planned pre-operative radiotherapy receive additional radiotherapy. After completion of study therapy, patients are followed up periodically for 10 years.

OBJECTIVES:

       -  To collect biological specimens from patients with osteosarcoma at Children's Oncology Group (COG) institutions.

       -  To provide a repository for long-term storage of osteosarcoma-related biological materials.

       -  To make these specimens available to qualified researchers to understand the biology of osteosarcoma and correlate these results with the patients' clinical data.

     OUTLINE: After the initial submission of blood samples, patients may undergo open or closed biopsy in order to obtain fresh and frozen tissue samples as well as paraffin embedded material. Patients who are enrolled at the time of initial diagnosis but then have a definitive surgery or develop recurrent disease may submit additional samples (paraffin block, frozen and fresh tumor tissue, or slides together with blood samples). Autopsy tumor samples may also be submitted.

OBJECTIVES: I. Collect human tumor tissue and other biological specimens (blood, serum, and bone marrow) from patients with rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma diagnosed and/or treated at a Children's Oncology Group (COG) member institution. II. Provide a repository for storage of tissue and other biological specimens collected by COG investigators from these patients. III. Make these specimens available for approved projects by laboratory-based investigators. IV. Collect clinical data on these patients who are not being treated on a COG therapeutic study. V. Define and compare the clinical features of patient subgroups with alveolar rhabdomyosarcoma whose tumors carry the t(2;13), t(1;13) or neither translocation. VI. Investigate the relationship between evidence of submicroscopic disease and response rate (CR/PR), failure-free survival, and survival of patients with alveolar rhabdomyosarcoma, as determined by positive or negative reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the t(2:13) and t(1:13) on peripheral blood and bone marrow specimens obtained at diagnosis. VII. Compare the clinical, cytogenetic, and molecular biologic features of patient subgroups with anaplastic rhabdomyosarcoma and other subtypes of rhabdomyosarcoma. OUTLINE: Surgical tissue, bone marrow, and blood specimens are collected at diagnosis (initial or relapse) and, if applicable, at the development of a second primary tumor. Specimens are used for research purposes. A certificate of confidentiality protecting the identity of research participants in this project has been issued by the National Cancer Institute. Patients who are not enrolled on a Children's Oncology Group treatment trial are followed every 6 months for at least 10 years or until disease progression or development of a second malignancy.

OBJECTIVES:

     Primary

       -  Compare the event-free and overall survival of patients with tumor of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery.

     Secondary

       -  Determine the prognostic significance of EWS-Flil transcript in these patients.

       -  Determine the frequency and prognostic value of minimal disease in bone marrow and PBSC, as determined by the presence or absence of EWS-Flil transcript, in these patients.

       -  Determine the feasibility and toxicity of VIDE induction chemotherapy in these patients.

       -  Determine the response of these patients to VIDE induction chemotherapy.

       -  Determine the feasibility and toxicity of VAI consolodation chemotherapy in these patients.

       -  Determine the feasibility and toxicity of Bu-Mel consolodation chemotherapy in these patients.

       -  Determine event-free survival and overall survival of patients treated with these regimens by prognostic group analysis.

     OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and local treatment of the primary tumor (yes vs no).

     Patients receive induction chemotherapy comprising vincristine IV on day 1 and ifosfamide IV over 3 hours, doxorubicin IV over 4 hours, and etoposide IV over 1 hour on days 1-3 (VIDE). Treatment repeats every 21 days for 4 courses in the absence of unacceptable toxicity. Peripheral blood stem cells (PBSC) are collected after course 3 and/or 4. Patients are evaluated after course 4. Patients in need of early radiotherapy due to an axial tumor or patients who require radiotherapy to the brain and/or spinal cord (at any time during study) are assigned to group 1. Patients not needing early radiotherapy are assigned to group 2.

       -  Group 1: Patients receive 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Patients requiring radiotherapy to the axial tumor also undergo concurrent radiotherapy 5 days a week. Some patients may then undergo surgical resection of the tumor. All patients will then receive vincristine IV on day 1 and dactinomycin IV and ifosfamide IV over 3 hours on days 1 and 2 (VAI). Treatment repeats every 21 days for 8 courses (courses 7-14). Patients requiring radiotherapy to the brain and/or spinal cord also undergo concurrent radiotherapy.

       -  Group 2: Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients are randomized to 1 of 2 consolidation therapy arms.

            -  Arm I: Patients receive 7 additional courses of VAI chemotherapy (courses 8-14). Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent whole-lung radiotherapy for 6-12 days.

            -  Arm II: Patients receive high-dose chemotherapy comprising oral busulfan every 6 hours on days -6 to -3 and melphalan IV over 30 minutes on day -2. Patients receive autologous PBSC IV on day 0. Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent radiotherapy 5 days a week for at least 5 weeks.

     Patients are followed every 3 months for 4 years, every 6 months for 1 year, and then periodically thereafter.

     Peer Reviewed and Funded or Endorsed by Cancer Research UK

     PROJECTED ACCRUAL: Approximately 1,200 patients will be accrued for this study within approximately 7 years.

PRIMARY OBJECTIVES: I. To determine the objective response rate to sorafenib tosylate (sorafenib) in children with relapsed or refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma (HCC), or papillary thyroid carcinoma (PTC). SECONDARY OBJECTIVES: I. To further define and describe the toxicities of sorafenib administered on an oral, twice-daily continuous schedule. II. To further characterize the pharmacokinetics of sorafenib in children with refractory cancer. III. To estimate the progression-free survival on sorafenib for rhabdomyosarcoma, Wilms tumor, and hepatocellular carcinoma and compare to a group of patients enrolled on selected closed Phase II studies of Children Oncology Group (COG). IV. To assess the biologic activity of sorafenib on vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor-2 (VEGFR-2) in peripheral blood samples. (Exploratory) V. To evaluate the presence of BRAF mutations and RET/PTC rearrangements in patients with PTC. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (rhabdomyosarcoma vs Wilms tumor vs hepatocellular carcinoma vs papillary thyroid carcinoma). Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic studies, and VEGF and VEGFR-2 analysis by ELISA. Previously collected formalin-fixed paraffin-embedded tissue samples, from patients with papillary thyroid carcinoma, are also analyzed for BRAF mutation and RET/PTC rearrangements by PCR. After completion of study treatment, patients are followed up for up to 5 years.