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
Conditions
Brief 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.
Detailed description
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.
Interventions
DRUGCyclophosphamide
Given IV
DRUGDoxorubicin
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
DRUGEtoposide Phosphate
Given IV
RADIATIONExternal Beam Radiation Therapy
Undergo EBRT
BIOLOGICALGanitumab
Given IV
DRUGIfosfamide
Given IV
RADIATIONStereotactic Radiosurgery
Undergo SBRT
PROCEDURETherapeutic Surgical Procedure
Undergo surgery
DRUGVincristine
Given IV
DRUGVincristine Sulfate
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5 years after enrollment | Time from study enrollment to death or last patient contact. |
| Frequency of Toxicity-events | Up to 202 days | 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. |
Countries
Canada, Puerto Rico, United States
Contacts
PRINCIPAL_INVESTIGATORSteven G DuBois
Children's Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A (VDC/IE) 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 | 157 |
| 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.
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 | 155 |
| Total | 312 |
Baseline characteristics
| Characteristic | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 124 Participants | 123 Participants | 247 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 32 Participants | 65 Participants |
| Age, Continuous | 14.89 years | 15.16 years | 15.03 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 23 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 116 Participants | 229 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 16 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 21 Participants | 38 Participants |
| Race (NIH/OMB) White | 128 Participants | 125 Participants | 253 Participants |
| Region of Enrollment Canada | 10 participants | 11 participants | 21 participants |
| Region of Enrollment China | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Guatemala | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Puerto Rico | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 144 participants | 142 participants | 286 participants |
| Sex: Female, Male Female | 71 Participants | 69 Participants | 140 Participants |
| Sex: Female, Male Male | 86 Participants | 86 Participants | 172 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 61 / 145 | 67 / 150 |
| other Total, other adverse events | 114 / 145 | 122 / 150 |
| serious Total, serious adverse events | 3 / 145 | 45 / 150 |
Outcome results
Primary
Event-free Survival
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 frame: 5 years after enrollment
Population: Only eligible patients are considered in the calculation of this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A (VDC/IE) | Event-free Survival | 30.88 percent probability of participants |
| Regimen B (VDC/IE + Ganitumab) | Event-free Survival | 30.4 percent probability of participants |
Secondary
Frequency of Toxicity-events
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.
Time frame: Up to 202 days
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A (VDC/IE) | Frequency of Toxicity-events | 10 Reporting Periods |
| Regimen B (VDC/IE + Ganitumab) | Frequency of Toxicity-events | 27 Reporting Periods |
Secondary
Overall Survival
Time from study enrollment to death or last patient contact.
Time frame: 5 years after enrollment
Population: Only eligible patients are considered in the calculation of this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A (VDC/IE) | Overall Survival | 44.93 Percent Probability |
| Regimen B (VDC/IE + Ganitumab) | Overall Survival | 48.19 Percent Probability |
Other Pre-specified
Circulating Tumor DNA (ctDNA) Testing
Will report the proportion of patients that have a change in translocation result associated with ctDNA testing across time periods.
Time frame: Up to 202 days
Other Pre-specified
EWS Translocation
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.
Time frame: Up to 10 years
Other Pre-specified
Frequency of Resolution of Bone Marrow Metastases
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.
Time frame: Up to 84 days
Other Pre-specified
Frequency of Toxicity Events During Ganitumab Maintenance
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.
Time frame: Up to 307 days
Other Pre-specified
Germline Polymorphisms in EGFR
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.
Time frame: Up to 10 years
Other Pre-specified
Occurrence of Sinusoidal Obstructive Disease (SOS) Associated With the Addition of Ganitumab to VDC/IE
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.
Time frame: Up to 202 days
Other Pre-specified
Proportion of Patients Who Successfully Receive Planned Stereotactic Body Radiotherapy (SBRT)
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.
Time frame: 202 days
Other Pre-specified
Serial Genomic Profiling
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.
Time frame: Up to 307 days
Other Pre-specified
Serum IGF Pathway Component and Tissue Protein, Deoxyribonucleic Acid (DNA), and Ribonucleic Acid Markers
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.
Time frame: Up to 10 years
Other Pre-specified
Trough Levels of Serum Ganitumab
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.
Time frame: Up to 15 days
Other Pre-specified
Tumor Cell Surface IGF-1R Expression
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.
Time frame: Up to 307 days