Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma
Condition: Metastatic Ewing Sarcoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Bone Marrow; Metastatic Malignant Neoplasm in the Lung; Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues
MeSH terms: Neoplasms; Sarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neoplasms, Second Primary; Neuroectodermal Tumors, Primitive, Peripheral; Bone Neoplasms; Neoplasm Metastasis; Soft Tissue Neoplasms; Bone Marrow Diseases
Intervention: Cyclophosphamide; Doxorubicin; Doxorubicin Hydrochloride; Etoposide; Etoposide Phosphate; External Beam Radiation Therapy; Ganitumab; Ifosfamide; Stereotactic Radiosurgery; Therapeutic Surgical Procedure; Vincristine; Vincristine Sulfate
Intervention description: Given IV; Given IV; Given IV; Given IV; Given IV; Undergo EBRT; Given IV; Given IV; Undergo SBRT; Undergo surgery; Given IV; Given IV
Intervention MeSH terms: Cyclophosphamide; Ifosfamide; Isophosphamide mustard; Doxorubicin; Liposomal doxorubicin; Etoposide; Etoposide phosphate; Vincristine; Daunorubicin; Podophyllotoxin; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 312.0
Sex: All
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial studies how well combination chemotherapy with or without
      ganitumab works in treating patients with newly diagnosed Ewing sarcoma that has spread to
      other parts of the body. Treatment with drugs that block the IGF-1R pathway, such as
      ganitumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in
      chemotherapy, such as vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide,
      work in different ways to stop the growth of tumor cells, either by killing the cells, by
      stopping them from dividing, or by stopping them from spreading. It is not yet known whether
      adding ganitumab to combination chemotherapy is more effective in treating patients with
      newly diagnosed metastatic Ewing sarcoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed
             Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) arising from bone
             or soft tissue and with metastatic disease involving lung, bone, bone marrow, or other
             metastatic site

          -  For the purpose of this study metastatic disease is defined as one or more of the
             following:

               -  Lesions which are discontinuous from the primary tumor, are not regional lymph
                  nodes, and do not share a bone or body cavity with the primary tumor; skip
                  lesions in the same bone as the primary tumor do not constitute metastatic
                  disease; skip lesions in an adjacent bone are considered bone metastases; if
                  there is any doubt whether lesions are metastatic, a biopsy of those lesions
                  should be performed

               -  Contralateral pleural effusion and/or contralateral pleural nodules

               -  Distant lymph node involvement

               -  Patients with pulmonary nodules are considered to have metastatic disease if the
                  patient has:

                    -  Solitary nodule >= 0.5 cm or multiple nodules of >= 0.3 cm unless lesion is
                       biopsied and negative for tumor

                    -  Patients with solitary nodule < 0.5 cm or multiple nodules < 0.3 cm are not
                       considered to have lung metastasis unless biopsy documents tumor

               -  Bone marrow metastatic disease is based on morphologic evidence of Ewing sarcoma
                  based on hematoxylin and eosin (H&E) stains; in the absence of morphologic
                  evidence of marrow involvement on H&E, patients with bone marrow involvement
                  detected ONLY by flow cytometry, reverse-transcriptase (RT)-polymerase chain
                  reaction (PCR), fluorescence in situ hybridization (FISH), or
                  immunohistochemistry will NOT be considered to have clinical bone marrow
                  involvement for the purposes of this study

                    -  This study requires bilateral bone marrow biopsies at study entry; the
                       suggested approach for patients with large pelvic tumors in which a
                       posterior iliac crest bone marrow biopsy would track through the tumor is to
                       instead undergo 2 marrow biopsies on the contralateral side (either 2
                       posterior biopsies or one posterior and one anterior biopsy)

               -  Bone metastasis: This study utilizes whole body FDG-PET scans to screen patients
                  for bone metastases; areas suspicious for bone metastasis based on FDG-PET scans
                  require confirmatory anatomic imaging with either MRI or computed tomography (CT)
                  (whole body FDG-PET/CT or FDG-PET/magnetic resonance [MR] scan acceptable); whole
                  body technetium bone scans may be performed at the discretion of the investigator
                  and are not required; for patients without other sites of metastatic disease
                  whose sole metastatic site to qualify for study entry is a single area suspicious
                  for bone metastasis identified by FDG-PET, confirmatory biopsy or anatomic
                  imaging evidence of an associated soft tissue mass at that site is required for
                  study entry

          -  Patients must have adequate tumor tissue to meet the minimum requirement for
             submission

          -  Enrolling institutions are reminded that submission of pre-treatment serum, tumor
             tissue and whole blood is required

          -  Patients should only have had a biopsy of the primary tumor without an attempt at
             complete or partial resection; patients will still be eligible if excision was
             attempted or accomplished as long as adequate anatomic imaging (MRI for most primary
             tumor sites) was obtained prior to surgery

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (performed within
             7 days prior to enrollment):

               -  Age < 6 months: Maximum serum creatinine (mg/dL): 0.4 for males and females

               -  Age 6 months to < 1 year: Maximum serum creatinine (mg/dL): 0.5 for males and
                  females

               -  Age 1 to < 2 years: Maximum serum creatinine (mg/dL): 0.6 for males and females

               -  Age 2 to < 6 years: Maximum serum creatinine (mg/dL): 0.8 for males and females

               -  Age 6 to < 10 years: Maximum serum creatinine (mg/dL): 1 for males and females

               -  Age 10 to < 13 years: Maximum serum creatinine (mg/dL): 1.2 for males and females

               -  Age 13 to < 16 years: Maximum serum creatinine (mg/dL): 1.5 for males and 1.4 for
                  females

               -  Age >= 16 years: Maximum serum creatinine (mg/dL): 1.7 for males and 1.4 for
                  females

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days
             prior to enrollment), and

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x
             upper limit of normal (ULN) for age (performed within 7 days prior to enrollment)
             (except for patients with liver metastasis who may enroll if ALT < 5 times ULN for
             age)

          -  Shortening fraction of >= 27% or

          -  Ejection fraction of >= 50%

          -  Patients must have a normal blood sugar level for age to participate; if an initial
             random draw (ie. non-fasting) blood glucose value is out of range, it is acceptable to
             repeat this test as a fasting draw

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  Patients with regional node involvement as their only site of disease beyond the
             primary tumor will not be eligible

          -  Patients whose primary tumors arise in the intra-dural soft tissue (e.g. brain and
             spinal cord) are not eligible

          -  Patients who have received prior chemotherapy or radiation therapy are not eligible

          -  Female patients of childbearing potential are not eligible unless a negative pregnancy
             test result has been obtained; lactating females are not eligible unless they have
             agreed not to breastfeed their infants for the duration of protocol therapy; sexually
             active patients of reproductive potential are not eligible unless they have agreed to
             use an effective contraceptive method for the duration of protocol therapy

          -  Patients with known pre-existing diabetes mellitus will be excluded from study

          -  Patients receiving chronic pharmacologic doses of corticosteroids are not eligible;
             for the purposes of eligibility, chronic exposure is defined as anticipated exposure
             of > 3 weeks, including the sum of both pre-enrollment and anticipated post-enrollment
             dosing; patients on acute corticosteroid therapy (=< 3 weeks of total planned
             exposure) must still meet the normal blood glucose requirement; patients receiving
             chronic inhaled corticosteroids or chronic physiologic replacement doses of
             corticosteroids are eligible