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Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma
This study is currently recruiting participants.
Verified May 2017 by National Cancer Institute (NCI)
Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02306161
First received: December 1, 2014
Last updated: July 21, 2017
Last verified: May 2017
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Purpose
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. Monoclonal antibodies, such as ganitumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as vincristine sulfate, doxorubicin hydrochloride, 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 combination chemotherapy is more effective with or without ganitumab in treating patients with newly diagnosed Ewing sarcoma.
| Condition | Intervention | Phase |
|---|---|---|
| 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 | Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Radiation: External Beam Radiation Therapy Biological: Ganitumab Drug: Ifosfamide Other: Laboratory Biomarker Analysis Other: Pharmacological Study Radiation: Stereotactic Radiosurgery Procedure: Therapeutic Surgical Procedure Drug: Vincristine Sulfate | Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: No masking Primary Purpose: Treatment |
| Official Title: | 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 |
Resource links provided by NLM:
Genetics Home Reference related topics:
Ewing sarcoma
MedlinePlus related topics:
Soft Tissue Sarcoma
Genetic and Rare Diseases Information Center resources:
Soft Tissue Sarcoma
Ewing Sarcoma
Ewing's Family of Tumors
Neuroepithelioma
Osteosarcoma
U.S. FDA Resources
Further study details as provided by National Cancer Institute (NCI):
Primary Outcome Measures:
- Time to adverse analytic event (EFS), defined to be disease-related event, diagnosis of a second malignant neoplasm, or death [ Time Frame: From the time of randomization, assessed up to 10 years ]The two regimens will be compared using the relative risk regression model with strata representing those used for randomization. A log-partial-likelihood one-sided test of size 0.20 will be used to compare the two regimens. A parametric model that treats disease progressions identified at routine visits as interval censored observations with the left censoring time as the date of the last screening prior to the identification of the relapse and other relapse times as being known exactly will be fit.
Secondary Outcome Measures:
- Bone marrow response rates [ Time Frame: Up to 10 years ]Each bone marrow evaluable patient will be assessed for the presence or absence of bone marrow metastatic disease over the interval between enrollment and the time of first local control measure or the end of the Induction reporting period, whichever comes first. Only one evaluation of best response will be used to classify the patient as complete responder (no evidence of marrow disease) or incomplete responder (residual marrow disease or progression). An estimate of the proportion of patients who achieve complete bone marrow response and an associated 95% confidence interval provided.
- Feasibility of SBRT, defined as an individual that has SBRT planned for at least one site, starts the treatment of metastatic disease phase of the protocol and has at least 85% of tumor sites planned to be treated with SBRT receive successful SBRT [ Time Frame: Up to 10 years ]Successful treatment delivery is defined as a treatment plan that is acceptable or has only minor variation as assessed by Imaging and Radiation Oncology Core (IROC) Rhode Island (formerly Quality Assurance Review Center [QARC]). In addition to this feasibility assessment, efficacy will be evaluated by comparing the failure rate at irradiated bone metastases with SBRT and EBRT, recognizing selection bias between patients treated with SBRT or EBRT.
- Ganitumab pharmacokinetics (PK) [ Time Frame: Pre-dose, prior to the second dose of ganitumab on Induction day 15, prior to the third dose of ganitumab on Induction day 29, prior to the sixth dose of ganitumab on Induction day 71 (Induction), and weeks 1, 7, 10, and 16 (maintenance) ]Results of this PK testing will be reported descriptively, with an emphasis on the proportion of patients achieving a trough serum ganitumab concentration >= 10 µg/mL at a dose of 18 mg/kg IV every 3 weeks. Additional trough levels in Maintenance will allow for estimation of accumulation, half-life, and steady state clearance of ganitumab.
- Overall Survival [ Time Frame: From the time of randomization, assessed up to 10 years ]
- Overall toxicity of the addition of ganitumab to VDC/IE chemotherapy, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after last dose of study drug ]The 95% confidence interval for the toxicity-event rate for each phase noted above for patients enrolled on the comparator therapy will be constructed.
- Risk of death [ Time Frame: Up to 10 years ]The relative risk for death and the naïve p-value associated with the null hypothesis H0: relative risk for death is 1 will be estimated using the stratified partial likelihood for the relative risk regression model accounting for the factors used to stratify randomization at the time full information is obtained for the EFS comparison.
- Sinusoidal obstructive disease (SOS) associated with the addition of ganitumab to VDC/IE [ Time Frame: Up to 30 days after last dose of study drug ]A phase where a patient experiences any SOS will be considered a phase with an SOS toxicity-event. The effect of possible correlations between analytic units that arises because some analytic units are contributed by the same individual will be explored. A random effects binomial model where a Normally distributed random effect with 0 mean and unknown variance chi-squared is contributed by each unit in a pair of analytic units that arise from the same individual will be explored.
- Tolerability of maintenance ganitumab [ Time Frame: Up to 10 years ]At the time each study progress report is prepared, the toxicity-event rate will be calculated and the one-sided test of size 0.05 of the null hypothesis that the toxicity-event rate is 25% will be performed.
Other Outcome Measures:
- Circulating tumor DNA (ctDNA) testing [ Time Frame: Up to 10 years ]Will report the proportion of patients that have a change in translocation result associated with ctDNA testing across time periods.
- EWS translocation [ Time Frame: Up to 10 years ]The institutional result of EWS tumor testing will be categorized as translocation detected (yes v. no) and the type of translocation detected will also be recorded. The proportion of patients with a particular EWS translocation variant will be tabulated. Risk for EFS-event will be compared across groups defined by translocation positivity using the log rank test.
- Germline polymorphisms in EGFR [ Time Frame: Up to 10 years ]EFS will be compared between patients with and without the presence of the minor allele using the log rank test, both for the entire patient population and for patients randomized to ganitumab. In addition to the log rank test we will use the modeling approach described above for the primary study comparison. Additional analyses will compare overall survival and objective bone marrow response rate prior to local control as clinical outcomes of interest. In addition, an association between the number of copies of the minor allele and these clinical endpoints will be evaluated.
- Serial genomic profiling identified by flow cytometry [ Time Frame: Up to 10 years ]Profiles will be presented graphically, and samples obtained from different sites of tumor within the same individual will also be presented.
- Serum IGF pathway component and tissue protein, DNA, and RNA markers [ Time Frame: Up to 10 years ]In addition to the log rank test the modeling approach will be used for the primary study comparison. Linear trend in EFS-risk will be investigated by segregating the marker level according to quartiles. For bone marrow response rate analyses, Fisher's exact test will be used to compare the objective bone marrow response rate (complete response vs. incomplete response) at start of local control between patients with biomarker levels above and below the group median.
- Tumor cell surface IGF-1R expression [ Time Frame: Up to 10 years ]The percentage of patients with detectable bone marrow micrometastatic disease at baseline who clear their bone marrow micrometastatic disease after three and six cycles of study therapy will be reported descriptively according to treatment arm. Extent of tumor cell IGF-1R co-expression will also be reported. Moreover, the change in tumor cell IGF-1R co-expression in patients treated with and without ganitumab will be reported descriptively.
| Estimated Enrollment: | 330 |
| Actual Study Start Date: | December 8, 2014 |
| Estimated Primary Completion Date: | December 31, 2018 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Regimen A (VDC/IE)
INDUCTION THERAPY: Patients receive vincristine sulfate IV over 1 minute on day 1; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2; and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 5, and 9; and ifosfamide IV over 1 hour on days 1 to 5 and etoposide IV over 1-2 hours on days 1 to 5 of weeks 3, 7, and 11. LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1, 7, 9, and 13; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of weeks 1 and 7; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 7, 9, and 13; ifosfamide IV over 1 hour on days 1 to 5 of weeks 3, 5, 11, and 15; and etoposide IV over 1-2 hours on days 1 to 5 of weeks 3, 5, 11, and 15. METASTATIC SITE IRRADIATION: Patients with lung metastases undergo definitive SBRT or EBRT over 5 days. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Radiation: External Beam Radiation Therapy
Undergo EBRT
Other Names:
Drug: Ifosfamide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Radiation: Stereotactic Radiosurgery
Undergo SBRT
Other Names:
Procedure: Therapeutic Surgical Procedure
Undergo surgery
Drug: Vincristine Sulfate
Given IV
Other Names:
|
|
Experimental: 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 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 definitive SBRT or EBRT over 5 days. MAINTENANCE THERAPY: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 in weeks 1, 4, 7, 10, 13, 16, 19, and 22. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Radiation: External Beam Radiation Therapy
Undergo EBRT
Other Names:
Biological: Ganitumab
Given IV
Other Names:
Drug: Ifosfamide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Radiation: Stereotactic Radiosurgery
Undergo SBRT
Other Names:
Procedure: Therapeutic Surgical Procedure
Undergo surgery
Drug: Vincristine Sulfate
Given IV
Other Names:
|
Show Detailed Description
Eligibility| Ages Eligible for Study: | up to 50 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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:
- 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, and
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x upper limit of normal (ULN) for age (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 (eg. 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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT02306161
Show 299 Study Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT02306161
Show 299 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Steven DuBois | Children's Oncology Group |
More Information
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02306161 History of Changes |
| Other Study ID Numbers: |
NCI-2014-02380 NCI-2014-02380 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) AEWS1221 AEWS1221 ( Other Identifier: Childrens Oncology Group ) AEWS1221 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
| Study First Received: | December 1, 2014 |
| Last Updated: | July 21, 2017 |
Additional relevant MeSH terms:
|
Neoplasms Sarcoma Sarcoma, Ewing Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Neuroectodermal Tumors, Primitive, Peripheral Neoplasms, Second Primary Bone Neoplasms Bone Marrow Diseases Neoplasm Metastasis Lung Neoplasms Soft Tissue Neoplasms Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Osteosarcoma |
Neoplasms, Bone Tissue Neoplasms, Connective Tissue Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial Neoplasms, Glandular and Epithelial Neoplasms by Site Bone Diseases Musculoskeletal Diseases Hematologic Diseases Neoplastic Processes Pathologic Processes Respiratory Tract Neoplasms Thoracic Neoplasms Lung Diseases |
ClinicalTrials.gov processed this record on July 24, 2017