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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.

Doxorubicin Hydrochloride

Etoposide Phosphate

External Beam Radiation Therapy

Ganitumab

Stereotactic Radiosurgery

Therapeutic Surgical Procedure

Vincristine Sulfate

Steven G DuBois

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.

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.

EXPLORATORY OBJECTIVES:

I. To compare bone marrow response rates in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab.

II. To describe the toxicity of 6 months of ganitumab monotherapy as maintenance therapy following multimodality therapy in patients with newly diagnosed metastatic Ewing sarcoma.

III. To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma \< 21 years of age treated with 18 mg/kg.

IV. To describe the feasibility of and local failure rates following hypofractionated stereotactic body radiotherapy (SBRT) directed at bone metastases in patients with newly diagnosed metastatic Ewing sarcoma.

V. To determine if EFS, overall survival, bone marrow response rates, and toxicity differ based on serum markers of the insulin-like growth factor 1 (IGF-1) pathway in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab.

VI. To determine if EFS, overall survival, and bone marrow response rates differ based on protein, deoxyribose nucleic acid (DNA), and ribonucleic acid (RNA) marker in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab.

VII. To evaluate bone marrow micrometastatic disease and tumor cell surface IGF-1R expression at diagnosis and after 3 and 6 cycles of study therapy in patients with newly diagnosed metastatic Ewing sarcoma.

VIII. To determine if the presence of germline polymorphisms in EGFR correlate with response to multiagent therapy with and without ganitumab.

IX. To investigate the ability of fludeoxyglucose F 18-positron emission tomography (FDG-PET) to augment conventional response assessment of primary Ewing sarcoma tumors by magnetic resonance imaging (MRI).

X. To explore FDG-PET response at the primary tumor as a prognostic marker and as a predictive biomarker of clinical activity of IGF-1R inhibition in patients with newly diagnosed metastatic Ewing sarcoma.

XI. To collect data on institutional testing for Ewing sarcoma breakpoint region 1 (EWSR1) translocation status in patients enrolling on study.

XII. To explore the capacity of plasma cell-free DNA analysis to detect tumor-specific genetic changes at initial diagnosis and after initiation of protocol therapy.

XIII. To collect a population of bone marrow metastatic tumor cells by flow cytometry for genomic profiling.

OUTLINE: Patients are randomized to 1 of 2 treatment regimens. (As of 3/20/2019, the study is closed to accrual and patients in Regimen B no longer receive ganitumab.)

REGIMEN A (vincristine sulfate, doxorubicin hydrochloride and cyclophosphamide \[VDC\] and ifosfamide and etoposide phosphate \[IE\]):

INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (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 phosphate 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 phosphate 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 whole lung radiation and patients with bone metastases undergo definitive SBRT or external beam radiation therapy (EBRT).

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.

After completion of study treatment, patients are followed for 10 years.

Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma

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

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.

Extent of tumor cell IGF-1R co-expression will also be reported. Change in tumor cell IGF-1R co-expression in patients treated with and without ganitumab will be reported descriptively.

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.

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.

Will report the proportion of patients that have a change in translocation result associated with ctDNA testing across time periods.

Will be identified by flow cytometry. Profiles will be presented graphically, and samples obtained from different sites of tumor within the same individual will also be presented.

The number of induction and maintenance cycles received by patients randomized to the experimental therapy where SOS is observed. Only patients who receive all reporting period therapy or experience SOS will contribute to this outcome measure.

The number of patients who are enrolled with bone marrow metastases whose bone marrow disease is not detected after evaluation at the time of of first local control measure or the end of the Induction reporting period, whichever comes first. Only eligible patients who receive at least one dose of randomized treatment assignment will be considered for this measure.

The number of induction or consolidation reporting periods in which a CTC version 4 codeable non-hematological adverse event, grade 3 left ventricular systolic dysfunction or the reporting period is terminated because of a CTC codeable event.

Trough levels of serum ganitumab prior to the second dose of ganitumab during induction obtained will be categorized as less than 10 micrograms per milliliter or greater than or equal to 10 micrograms per milliliter. This analysis will be conducted for the first 10 eligible patients who receive ganitumab.

A patient who has SBRT planned for at least one metastatic site and receives successful SBRT treatment to at least 85% of metastatic sites in the treatment plan. Successful treatment is determined by IROC review criteria. Only eligible patients start the metastatic site radiation reporting period will be considered for this outcome measure.

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.

Time from study enrollment to death or last patient contact.

The number of induction or consolidation reporting periods in which a CTC version 4 codeable grade 4 or greater non-hematological adverse event, grade 3 or greater left ventricular systolic dysfunction or the reporting period is terminated because of a CTC codeable event.

National Cancer Institute (NCI)

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients and those who did not receive therapy are excluded. All-Cause Mortality includes all deaths collected on the study.

INDUCTION THERAPY: Patients receive Induction therapy with alternating cycles of VDC and IE given every 2 weeks for 6 cycles.

LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy.

CONSOLIDATION THERAPY: Patients receive Consolidation therapy with alternating cycles of VDC and IE given every 2 weeks for 8 cycles.

METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT.

Cyclophosphamide: Given IV

Doxorubicin: Given IV

Doxorubicin Hydrochloride: Given IV

Etoposide: Given IV

Etoposide Phosphate: Given IV

External Beam Radiation Therapy: Undergo EBRT

Ifosfamide: Given IV

Stereotactic Radiosurgery: Undergo SBRT

Therapeutic Surgical Procedure: Undergo surgery

Vincristine: Given IV

Vincristine Sulfate: Given IV

Regimen A (VDC/IE)

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.

Cyclophosphamide: Given IV

Doxorubicin: Given IV

Doxorubicin Hydrochloride: Given IV

Etoposide: Given IV

Etoposide Phosphate: Given IV

External Beam Radiation Therapy: Undergo EBRT

Ganitumab: Given IV

Ifosfamide: Given IV

Stereotactic Radiosurgery: Undergo SBRT

Therapeutic Surgical Procedure: Undergo surgery

Vincristine: Given IV

Vincristine Sulfate: Given IV

Regimen B (VDC/IE + Ganitumab)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

China

Guatemala

Puerto Rico

Region of Enrollment

Results Reporting Coordinator

Only eligible patients are considered in the calculation of this outcome measure.

Event-free Survival

Overall Survival

Only eligible patients who received at least one dose of assigned protocol therapy are considered in the calculation of this outcome measure. Five hundred twenty-seven (527) reporting periods were contributed by patients enrolled on Regimen A; Five hundred seventy-six 576 reporting periods were contributed by patients enrolled on Regimen B.

Frequency of Toxicity-events

Serum IGF Pathway Component and Tissue Protein, Deoxyribonucleic Acid (DNA), and Ribonucleic Acid Markers

Tumor Cell Surface IGF-1R Expression

Germline Polymorphisms in EGFR

EWS Translocation

Circulating Tumor DNA (ctDNA) Testing

Serial Genomic Profiling

Occurrence of Sinusoidal Obstructive Disease (SOS) Associated With the Addition of Ganitumab to VDC/IE

Frequency of Resolution of Bone Marrow Metastases

Frequency of Toxicity Events During Ganitumab Maintenance

Trough Levels of Serum Ganitumab

Proportion of Patients Who Successfully Receive Planned Stereotactic Body Radiotherapy (SBRT)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma	NCT02306161	Metastatic Ewin... Metastatic Mali... Metastatic Mali... Metastatic Mali... Metastatic Peri... Peripheral Prim...	Cyclophosphamid... Doxorubicin Doxorubicin Hyd... Etoposide Etoposide Phosp... External Beam R... Ganitumab Ifosfamide Stereotactic Ra... Therapeutic Sur... Vincristine Vincristine Sul...	- 50 Years	National Cancer Institute (NCI)
Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma	NCT02306161	Metastatic Ewin... Metastatic Mali... Metastatic Mali... Metastatic Mali... Metastatic Peri... Peripheral Prim...	Cyclophosphamid... Doxorubicin Doxorubicin Hyd... Etoposide Etoposide Phosp... External Beam R... Ganitumab Ifosfamide Stereotactic Ra... Therapeutic Sur... Vincristine Vincristine Sul...	- 50 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic peripheral primitive neuroectodermal tumor of bone