Randomized Phase 3 Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008) to Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 312
- 试验地点
- 573
- 主要终点
- Event-free Survival
研究概览
简要总结
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.
详细描述
PRIMARY OBJECTIVES:
I. To determine if event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy is improved with the addition of ganitumab (AMG 479).
SECONDARY OBJECTIVES:
I. To describe the toxicity of the addition of ganitumab to multimodality therapy for patients with newly diagnosed metastatic Ewing sarcoma.
II. To compare overall survival in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Regimen A (VDC/IE)
See Design Details.
干预措施: Cyclophosphamide (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Etoposide (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Doxorubicin Hydrochloride (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Vincristine (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Stereotactic Radiosurgery (Radiation)
Regimen A (VDC/IE)
See Design Details.
干预措施: Therapeutic Surgical Procedure (Procedure)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: External Beam Radiation Therapy (Radiation)
Regimen A (VDC/IE)
See Design Details.
干预措施: Vincristine Sulfate (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Etoposide (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Cyclophosphamide (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Vincristine (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Ifosfamide (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Etoposide Phosphate (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Ifosfamide (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Doxorubicin (Drug)
Regimen A (VDC/IE)
See Design Details.
干预措施: Doxorubicin Hydrochloride (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Ganitumab (Biological)
Regimen A (VDC/IE)
See Design Details.
干预措施: External Beam Radiation Therapy (Radiation)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Therapeutic Surgical Procedure (Procedure)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Etoposide Phosphate (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Stereotactic Radiosurgery (Radiation)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Vincristine Sulfate (Drug)
Regimen B (VDC/IE + ganitumab)
INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.
LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.
CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15.
METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.
MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.
干预措施: Doxorubicin (Drug)
结局指标
主要结局
Event-free Survival
时间窗: 5 years after enrollment
Estimated 5-year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Kaplan-Meier method is used for estimation. Patients without an event are censored at last contact.
次要结局
- Overall Survival(5 years after enrollment)
- Frequency of Toxicity-events(Up to 202 days)