Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
-
To describe the toxicity of the addition of ganitumab to multimodality therapy for patients with newly diagnosed metastatic Ewing sarcoma.
-
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:
-
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.
-
To describe the toxicity of 6 months of ganitumab monotherapy as maintenance therapy following multimodality therapy in patients with newly diagnosed metastatic Ewing sarcoma.
-
To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma < 21 years of age treated with 18 mg/kg.
-
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.
-
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.
-
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.
-
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.
-
To determine if the presence of germline polymorphisms in EGFR correlate with response to multiagent therapy with and without ganitumab.
-
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).
-
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.
-
To collect data on institutional testing for Ewing sarcoma breakpoint region 1 (EWSR1) translocation status in patients enrolling on study.
-
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.
-
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Regimen A (VDC/IE) See Design Details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Drug: Etoposide Phosphate
Given IV
Other Names:
Radiation: External Beam Radiation Therapy
Undergo EBRT
Other Names:
Drug: Ifosfamide
Given IV
Other Names:
Radiation: Stereotactic Radiosurgery
Undergo SBRT
Other Names:
Procedure: Therapeutic Surgical Procedure
Undergo surgery
Drug: Vincristine
Given IV
Other Names:
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 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. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Drug: Etoposide Phosphate
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:
Radiation: Stereotactic Radiosurgery
Undergo SBRT
Other Names:
Procedure: Therapeutic Surgical Procedure
Undergo surgery
Drug: Vincristine
Given IV
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Other Outcome Measures
- Serum IGF Pathway Component and Tissue Protein, Deoxyribonucleic Acid (DNA), and Ribonucleic Acid Markers [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 [Up to 307 days]
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.
- Germline Polymorphisms in EGFR [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.
- EWS Translocation [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.
- Circulating Tumor DNA (ctDNA) Testing [Up to 202 days]
Will report the proportion of patients that have a change in translocation result associated with ctDNA testing across time periods.
- Serial Genomic Profiling [Up to 307 days]
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.
- Occurrence of Sinusoidal Obstructive Disease (SOS) Associated With the Addition of Ganitumab to VDC/IE [Up to 202 days]
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.
- Frequency of Resolution of Bone Marrow Metastases [Up to 84 days]
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.
- Frequency of Toxicity Events During Ganitumab Maintenance [Up to 307 days]
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 [Up to 15 days]
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.
- Proportion of Patients Who Successfully Receive Planned Stereotactic Body Radiotherapy (SBRT) [202 days]
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.
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Alabama | Birmingham | Alabama | United States | 35233 |
| 2 | USA Health Strada Patient Care Center | Mobile | Alabama | United States | 36604 |
| 3 | Providence Alaska Medical Center | Anchorage | Alaska | United States | 99508 |
| 4 | Banner Children's at Desert | Mesa | Arizona | United States | 85202 |
| 5 | Phoenix Childrens Hospital | Phoenix | Arizona | United States | 85016 |
| 6 | Banner University Medical Center - Tucson | Tucson | Arizona | United States | 85719 |
| 7 | Yuma Regional Medical Center | Yuma | Arizona | United States | 85364 |
| 8 | CHI Saint Vincent Cancer Center Hot Springs | Hot Springs | Arkansas | United States | 71913 |
| 9 | Arkansas Children's Hospital | Little Rock | Arkansas | United States | 72202-3591 |
| 10 | Kaiser Permanente Downey Medical Center | Downey | California | United States | 90242 |
| 11 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 12 | Loma Linda University Medical Center | Loma Linda | California | United States | 92354 |
| 13 | Miller Children's and Women's Hospital Long Beach | Long Beach | California | United States | 90806 |
| 14 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 15 | Valley Children's Hospital | Madera | California | United States | 93636 |
| 16 | UCSF Benioff Children's Hospital Oakland | Oakland | California | United States | 94609 |
| 17 | Kaiser Permanente-Oakland | Oakland | California | United States | 94611 |
| 18 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
| 19 | Lucile Packard Children's Hospital Stanford University | Palo Alto | California | United States | 94304 |
| 20 | Sutter Medical Center Sacramento | Sacramento | California | United States | 95816 |
| 21 | University of California Davis Comprehensive Cancer Center | Sacramento | California | United States | 95817 |
| 22 | Rady Children's Hospital - San Diego | San Diego | California | United States | 92123 |
| 23 | UCSF Medical Center-Parnassus | San Francisco | California | United States | 94143 |
| 24 | UCSF Medical Center-Mission Bay | San Francisco | California | United States | 94158 |
| 25 | Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center | Torrance | California | United States | 90502 |
| 26 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
| 27 | Penrose-Saint Francis Healthcare | Colorado Springs | Colorado | United States | 80907 |
| 28 | Rocky Mountain Cancer Centers-Penrose | Colorado Springs | Colorado | United States | 80907 |
| 29 | Porter Adventist Hospital | Denver | Colorado | United States | 80210 |
| 30 | Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver | Colorado | United States | 80218 |
| 31 | Mercy Medical Center | Durango | Colorado | United States | 81301 |
| 32 | Southwest Oncology PC | Durango | Colorado | United States | 81301 |
| 33 | Mountain Blue Cancer Care Center | Golden | Colorado | United States | 80401 |
| 34 | Rocky Mountain Cancer Centers-Lakewood | Lakewood | Colorado | United States | 80228 |
| 35 | Saint Anthony Hospital | Lakewood | Colorado | United States | 80228 |
| 36 | Littleton Adventist Hospital | Littleton | Colorado | United States | 80122 |
| 37 | Longmont United Hospital | Longmont | Colorado | United States | 80501 |
| 38 | Rocky Mountain Cancer Centers-Longmont | Longmont | Colorado | United States | 80501 |
| 39 | Parker Adventist Hospital | Parker | Colorado | United States | 80138 |
| 40 | Rocky Mountain Cancer Centers-Parker | Parker | Colorado | United States | 80138 |
| 41 | Saint Mary Corwin Medical Center | Pueblo | Colorado | United States | 81004 |
| 42 | Rocky Mountain Cancer Centers - Pueblo | Pueblo | Colorado | United States | 81008 |
| 43 | Rocky Mountain Cancer Centers-Thornton | Thornton | Colorado | United States | 80260 |
| 44 | Connecticut Children's Medical Center | Hartford | Connecticut | United States | 06106 |
| 45 | Yale University | New Haven | Connecticut | United States | 06520 |
| 46 | Alfred I duPont Hospital for Children | Wilmington | Delaware | United States | 19803 |
| 47 | MedStar Georgetown University Hospital | Washington | District of Columbia | United States | 20007 |
| 48 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 49 | Golisano Children's Hospital of Southwest Florida | Fort Myers | Florida | United States | 33908 |
| 50 | University of Florida Health Science Center - Gainesville | Gainesville | Florida | United States | 32610 |
| 51 | Memorial Regional Hospital/Joe DiMaggio Children's Hospital | Hollywood | Florida | United States | 33021 |
| 52 | Nemours Children's Clinic-Jacksonville | Jacksonville | Florida | United States | 32207 |
| 53 | University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami | Florida | United States | 33136 |
| 54 | Nicklaus Children's Hospital | Miami | Florida | United States | 33155 |
| 55 | AdventHealth Orlando | Orlando | Florida | United States | 32803 |
| 56 | Arnold Palmer Hospital for Children | Orlando | Florida | United States | 32806 |
| 57 | Nemours Children's Hospital | Orlando | Florida | United States | 32827 |
| 58 | Nemours Children's Clinic - Pensacola | Pensacola | Florida | United States | 32504 |
| 59 | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida | United States | 33701 |
| 60 | Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa | Florida | United States | 33607 |
| 61 | Saint Mary's Hospital | West Palm Beach | Florida | United States | 33407 |
| 62 | Children's Healthcare of Atlanta - Egleston | Atlanta | Georgia | United States | 30322 |
| 63 | Augusta University Medical Center | Augusta | Georgia | United States | 30912 |
| 64 | Memorial Health University Medical Center | Savannah | Georgia | United States | 31404 |
| 65 | Straub Clinic and Hospital | Honolulu | Hawaii | United States | 96813 |
| 66 | Kaiser Permanente Moanalua Medical Center | Honolulu | Hawaii | United States | 96819 |
| 67 | Kapiolani Medical Center for Women and Children | Honolulu | Hawaii | United States | 96826 |
| 68 | Saint Luke's Cancer Institute - Boise | Boise | Idaho | United States | 83712 |
| 69 | Rush - Copley Medical Center | Aurora | Illinois | United States | 60504 |
| 70 | Lurie Children's Hospital-Chicago | Chicago | Illinois | United States | 60611 |
| 71 | University of Illinois | Chicago | Illinois | United States | 60612 |
| 72 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
| 73 | Carle on Vermilion | Danville | Illinois | United States | 61832 |
| 74 | Carle Physician Group-Effingham | Effingham | Illinois | United States | 62401 |
| 75 | Carle Physician Group-Mattoon/Charleston | Mattoon | Illinois | United States | 61938 |
| 76 | Loyola University Medical Center | Maywood | Illinois | United States | 60153 |
| 77 | Good Samaritan Regional Health Center | Mount Vernon | Illinois | United States | 62864 |
| 78 | Advocate Children's Hospital-Oak Lawn | Oak Lawn | Illinois | United States | 60453 |
| 79 | Advocate Children's Hospital-Park Ridge | Park Ridge | Illinois | United States | 60068 |
| 80 | Saint Jude Midwest Affiliate | Peoria | Illinois | United States | 61637 |
| 81 | Saint John's Hospital | Springfield | Illinois | United States | 62702 |
| 82 | Southern Illinois University School of Medicine | Springfield | Illinois | United States | 62702 |
| 83 | Memorial Medical Center | Springfield | Illinois | United States | 62781 |
| 84 | Carle Cancer Center | Urbana | Illinois | United States | 61801 |
| 85 | The Carle Foundation Hospital | Urbana | Illinois | United States | 61801 |
| 86 | Rush-Copley Healthcare Center | Yorkville | Illinois | United States | 60560 |
| 87 | Deaconess Clinic Downtown | Evansville | Indiana | United States | 47713 |
| 88 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
| 89 | Saint Vincent Hospital and Health Care Center | Indianapolis | Indiana | United States | 46260 |
| 90 | Franciscan Saint Anthony Health-Michigan City | Michigan City | Indiana | United States | 46360 |
| 91 | Woodland Cancer Care Center | Michigan City | Indiana | United States | 46360 |
| 92 | Chancellor Center for Oncology | Newburgh | Indiana | United States | 47630 |
| 93 | Medical Oncology and Hematology Associates-West Des Moines | Clive | Iowa | United States | 50325 |
| 94 | Mercy Cancer Center-West Lakes | Clive | Iowa | United States | 50325 |
| 95 | Alegent Health Mercy Hospital | Council Bluffs | Iowa | United States | 51503 |
| 96 | Greater Regional Medical Center | Creston | Iowa | United States | 50801 |
| 97 | Blank Children's Hospital | Des Moines | Iowa | United States | 50309 |
| 98 | Medical Oncology and Hematology Associates-Laurel | Des Moines | Iowa | United States | 50314 |
| 99 | Mercy Medical Center - Des Moines | Des Moines | Iowa | United States | 50314 |
| 100 | University of Iowa/Holden Comprehensive Cancer Center | Iowa City | Iowa | United States | 52242 |
| 101 | Mercy Medical Center-West Lakes | West Des Moines | Iowa | United States | 50266 |
| 102 | Flaget Memorial Hospital | Bardstown | Kentucky | United States | 40004 |
| 103 | Commonwealth Cancer Center-Corbin | Corbin | Kentucky | United States | 40701 |
| 104 | Saint Joseph Radiation Oncology Resource Center | Lexington | Kentucky | United States | 40504 |
| 105 | Saint Joseph Hospital East | Lexington | Kentucky | United States | 40509 |
| 106 | University of Kentucky/Markey Cancer Center | Lexington | Kentucky | United States | 40536 |
| 107 | Saint Joseph London | London | Kentucky | United States | 40741 |
| 108 | Jewish Hospital | Louisville | Kentucky | United States | 40202 |
| 109 | Norton Children's Hospital | Louisville | Kentucky | United States | 40202 |
| 110 | Saints Mary and Elizabeth Hospital | Louisville | Kentucky | United States | 40215 |
| 111 | UofL Health Medical Center Northeast | Louisville | Kentucky | United States | 40245 |
| 112 | Jewish Hospital Medical Center South | Shepherdsville | Kentucky | United States | 40165 |
| 113 | Children's Hospital New Orleans | New Orleans | Louisiana | United States | 70118 |
| 114 | Ochsner Medical Center Jefferson | New Orleans | Louisiana | United States | 70121 |
| 115 | Eastern Maine Medical Center | Bangor | Maine | United States | 04401 |
| 116 | Maine Children's Cancer Program | Scarborough | Maine | United States | 04074 |
| 117 | University of Maryland/Greenebaum Cancer Center | Baltimore | Maryland | United States | 21201 |
| 118 | Sinai Hospital of Baltimore | Baltimore | Maryland | United States | 21215 |
| 119 | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland | United States | 21287 |
| 120 | Walter Reed National Military Medical Center | Bethesda | Maryland | United States | 20889-5600 |
| 121 | Massachusetts General Hospital Cancer Center | Boston | Massachusetts | United States | 02114 |
| 122 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 123 | Baystate Medical Center | Springfield | Massachusetts | United States | 01199 |
| 124 | UMass Memorial Medical Center - University Campus | Worcester | Massachusetts | United States | 01655 |
| 125 | C S Mott Children's Hospital | Ann Arbor | Michigan | United States | 48109 |
| 126 | University of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan | United States | 48109 |
| 127 | Bronson Battle Creek | Battle Creek | Michigan | United States | 49017 |
| 128 | Wayne State University/Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
| 129 | Ascension Saint John Hospital | Detroit | Michigan | United States | 48236 |
| 130 | Hurley Medical Center | Flint | Michigan | United States | 48503 |
| 131 | Helen DeVos Children's Hospital at Spectrum Health | Grand Rapids | Michigan | United States | 49503 |
| 132 | Mercy Health Saint Mary's | Grand Rapids | Michigan | United States | 49503 |
| 133 | Spectrum Health at Butterworth Campus | Grand Rapids | Michigan | United States | 49503 |
| 134 | Bronson Methodist Hospital | Kalamazoo | Michigan | United States | 49007 |
| 135 | West Michigan Cancer Center | Kalamazoo | Michigan | United States | 49007 |
| 136 | Borgess Medical Center | Kalamazoo | Michigan | United States | 49048 |
| 137 | Mercy Health Mercy Campus | Muskegon | Michigan | United States | 49444 |
| 138 | Lakeland Hospital Niles | Niles | Michigan | United States | 49120 |
| 139 | Huron Medical Center PC | Port Huron | Michigan | United States | 48060 |
| 140 | Lake Huron Medical Center | Port Huron | Michigan | United States | 48060 |
| 141 | Spectrum Health Reed City Hospital | Reed City | Michigan | United States | 49677 |
| 142 | Beaumont Children's Hospital-Royal Oak | Royal Oak | Michigan | United States | 48073 |
| 143 | Lakeland Medical Center Saint Joseph | Saint Joseph | Michigan | United States | 49085 |
| 144 | Marie Yeager Cancer Center | Saint Joseph | Michigan | United States | 49085 |
| 145 | Munson Medical Center | Traverse City | Michigan | United States | 49684 |
| 146 | Essentia Health Cancer Center | Duluth | Minnesota | United States | 55805 |
| 147 | Children's Hospitals and Clinics of Minnesota - Minneapolis | Minneapolis | Minnesota | United States | 55404 |
| 148 | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota | United States | 55455 |
| 149 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
| 150 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
| 151 | Central Care Cancer Center - Bolivar | Bolivar | Missouri | United States | 65613 |
| 152 | Cox Cancer Center Branson | Branson | Missouri | United States | 65616 |
| 153 | Columbia Regional | Columbia | Missouri | United States | 65201 |
| 154 | Freeman Health System | Joplin | Missouri | United States | 64804 |
| 155 | Mercy Hospital Joplin | Joplin | Missouri | United States | 64804 |
| 156 | Children's Mercy Hospitals and Clinics | Kansas City | Missouri | United States | 64108 |
| 157 | Delbert Day Cancer Institute at PCRMC | Rolla | Missouri | United States | 65401 |
| 158 | Mercy Clinic-Rolla-Cancer and Hematology | Rolla | Missouri | United States | 65401 |
| 159 | Heartland Regional Medical Center | Saint Joseph | Missouri | United States | 64506 |
| 160 | Cardinal Glennon Children's Medical Center | Saint Louis | Missouri | United States | 63104 |
| 161 | Saint Louis Cancer and Breast Institute-South City | Saint Louis | Missouri | United States | 63109 |
| 162 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 163 | Mercy Hospital Saint Louis | Saint Louis | Missouri | United States | 63141 |
| 164 | Mercy Hospital Springfield | Springfield | Missouri | United States | 65804 |
| 165 | CoxHealth South Hospital | Springfield | Missouri | United States | 65807 |
| 166 | Nebraska Medicine-Bellevue | Bellevue | Nebraska | United States | 68123 |
| 167 | CHI Health Saint Francis | Grand Island | Nebraska | United States | 68803 |
| 168 | Heartland Hematology and Oncology | Kearney | Nebraska | United States | 68845 |
| 169 | CHI Health Good Samaritan | Kearney | Nebraska | United States | 68847 |
| 170 | Saint Elizabeth Regional Medical Center | Lincoln | Nebraska | United States | 68510 |
| 171 | Children's Hospital and Medical Center of Omaha | Omaha | Nebraska | United States | 68114 |
| 172 | Nebraska Medicine-Village Pointe | Omaha | Nebraska | United States | 68118 |
| 173 | Alegent Health Immanuel Medical Center | Omaha | Nebraska | United States | 68122 |
| 174 | Hematology and Oncology Consultants PC | Omaha | Nebraska | United States | 68122 |
| 175 | Alegent Health Bergan Mercy Medical Center | Omaha | Nebraska | United States | 68124 |
| 176 | Alegent Health Lakeside Hospital | Omaha | Nebraska | United States | 68130 |
| 177 | Creighton University Medical Center | Omaha | Nebraska | United States | 68131 |
| 178 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
| 179 | Midlands Community Hospital | Papillion | Nebraska | United States | 68046 |
| 180 | Carson Tahoe Regional Medical Center | Carson City | Nevada | United States | 89703 |
| 181 | Comprehensive Cancer Centers of Nevada-Horizon Ridge | Henderson | Nevada | United States | 89052 |
| 182 | University Medical Center of Southern Nevada | Las Vegas | Nevada | United States | 89102 |
| 183 | Sunrise Hospital and Medical Center | Las Vegas | Nevada | United States | 89109 |
| 184 | Ann M Wierman MD LTD | Las Vegas | Nevada | United States | 89128 |
| 185 | Alliance for Childhood Diseases/Cure 4 the Kids Foundation | Las Vegas | Nevada | United States | 89135 |
| 186 | Summerlin Hospital Medical Center | Las Vegas | Nevada | United States | 89144 |
| 187 | Hope Cancer Care of Nevada-Pahrump | Pahrump | Nevada | United States | 89048 |
| 188 | Renown Regional Medical Center | Reno | Nevada | United States | 89502 |
| 189 | Saint Mary's Regional Medical Center | Reno | Nevada | United States | 89503 |
| 190 | Radiation Oncology Associates | Reno | Nevada | United States | 89509 |
| 191 | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756 |
| 192 | Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 193 | Morristown Medical Center | Morristown | New Jersey | United States | 07960 |
| 194 | Saint Peter's University Hospital | New Brunswick | New Jersey | United States | 08901 |
| 195 | Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital | New Brunswick | New Jersey | United States | 08903 |
| 196 | Newark Beth Israel Medical Center | Newark | New Jersey | United States | 07112 |
| 197 | Saint Joseph's Regional Medical Center | Paterson | New Jersey | United States | 07503 |
| 198 | Albany Medical Center | Albany | New York | United States | 12208 |
| 199 | Montefiore Medical Center-Einstein Campus | Bronx | New York | United States | 10461 |
| 200 | Montefiore Medical Center-Weiler Hospital | Bronx | New York | United States | 10461 |
| 201 | Children's Hospital at Montefiore | Bronx | New York | United States | 10467 |
| 202 | Montefiore Medical Center - Moses Campus | Bronx | New York | United States | 10467 |
| 203 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 204 | Glens Falls Hospital | Glens Falls | New York | United States | 12801 |
| 205 | NYU Winthrop Hospital | Mineola | New York | United States | 11501 |
| 206 | The Steven and Alexandra Cohen Children's Medical Center of New York | New Hyde Park | New York | United States | 11040 |
| 207 | Laura and Isaac Perlmutter Cancer Center at NYU Langone | New York | New York | United States | 10016 |
| 208 | Mount Sinai Hospital | New York | New York | United States | 10029 |
| 209 | NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | New York | New York | United States | 10032 |
| 210 | University of Rochester | Rochester | New York | United States | 14642 |
| 211 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794 |
| 212 | State University of New York Upstate Medical University | Syracuse | New York | United States | 13210 |
| 213 | New York Medical College | Valhalla | New York | United States | 10595 |
| 214 | Mission Hospital | Asheville | North Carolina | United States | 28801 |
| 215 | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
| 216 | Carolinas Medical Center/Levine Cancer Institute | Charlotte | North Carolina | United States | 28203 |
| 217 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 218 | Wake Forest University Health Sciences | Winston-Salem | North Carolina | United States | 27157 |
| 219 | Sanford Broadway Medical Center | Fargo | North Dakota | United States | 58122 |
| 220 | Children's Hospital Medical Center of Akron | Akron | Ohio | United States | 44308 |
| 221 | Good Samaritan Hospital - Cincinnati | Cincinnati | Ohio | United States | 45220 |
| 222 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 223 | Bethesda North Hospital | Cincinnati | Ohio | United States | 45242 |
| 224 | TriHealth Cancer Institute-Westside | Cincinnati | Ohio | United States | 45247 |
| 225 | TriHealth Cancer Institute-Anderson | Cincinnati | Ohio | United States | 45255 |
| 226 | Rainbow Babies and Childrens Hospital | Cleveland | Ohio | United States | 44106 |
| 227 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 228 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 229 | Dayton Children's Hospital | Dayton | Ohio | United States | 45404 |
| 230 | ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital | Toledo | Ohio | United States | 43606 |
| 231 | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | United States | 73104 |
| 232 | Mercy Hospital Oklahoma City | Oklahoma City | Oklahoma | United States | 73120 |
| 233 | Legacy Emanuel Children's Hospital | Portland | Oregon | United States | 97227 |
| 234 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
| 235 | Lehigh Valley Hospital-Cedar Crest | Allentown | Pennsylvania | United States | 18103 |
| 236 | Lehigh Valley Hospital - Muhlenberg | Bethlehem | Pennsylvania | United States | 18017 |
| 237 | Geisinger Medical Center | Danville | Pennsylvania | United States | 17822 |
| 238 | Penn State Children's Hospital | Hershey | Pennsylvania | United States | 17033 |
| 239 | Drexel University School of Medicine | Philadelphia | Pennsylvania | United States | 19102 |
| 240 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 241 | Saint Christopher's Hospital for Children | Philadelphia | Pennsylvania | United States | 19134 |
| 242 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
| 243 | Rhode Island Hospital | Providence | Rhode Island | United States | 02903 |
| 244 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 245 | Prisma Health Richland Hospital | Columbia | South Carolina | United States | 29203 |
| 246 | Saint Francis Hospital | Greenville | South Carolina | United States | 29601 |
| 247 | BI-LO Charities Children's Cancer Center | Greenville | South Carolina | United States | 29605 |
| 248 | Saint Francis Cancer Center | Greenville | South Carolina | United States | 29607 |
| 249 | Sanford USD Medical Center - Sioux Falls | Sioux Falls | South Dakota | United States | 57117-5134 |
| 250 | T C Thompson Children's Hospital | Chattanooga | Tennessee | United States | 37403 |
| 251 | Memorial Hospital | Chattanooga | Tennessee | United States | 37404 |
| 252 | Pulmonary Medicine Center of Chattanooga-Hixson | Hixson | Tennessee | United States | 37343 |
| 253 | East Tennessee Childrens Hospital | Knoxville | Tennessee | United States | 37916 |
| 254 | Saint Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
| 255 | The Children's Hospital at TriStar Centennial | Nashville | Tennessee | United States | 37203 |
| 256 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 257 | Memorial GYN Plus | Ooltewah | Tennessee | United States | 37363 |
| 258 | Dell Children's Medical Center of Central Texas | Austin | Texas | United States | 78723 |
| 259 | Saint Joseph Regional Cancer Center | Bryan | Texas | United States | 77802 |
| 260 | Driscoll Children's Hospital | Corpus Christi | Texas | United States | 78411 |
| 261 | Medical City Dallas Hospital | Dallas | Texas | United States | 75230 |
| 262 | UT Southwestern/Simmons Cancer Center-Dallas | Dallas | Texas | United States | 75390 |
| 263 | El Paso Children's Hospital | El Paso | Texas | United States | 79905 |
| 264 | Cook Children's Medical Center | Fort Worth | Texas | United States | 76104 |
| 265 | Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center | Houston | Texas | United States | 77030 |
| 266 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 267 | Covenant Children's Hospital | Lubbock | Texas | United States | 79410 |
| 268 | UMC Cancer Center / UMC Health System | Lubbock | Texas | United States | 79415 |
| 269 | Texas Tech University Health Sciences Center-Lubbock | Lubbock | Texas | United States | 79430 |
| 270 | Children's Hospital of San Antonio | San Antonio | Texas | United States | 78207 |
| 271 | Methodist Children's Hospital of South Texas | San Antonio | Texas | United States | 78229 |
| 272 | University of Texas Health Science Center at San Antonio | San Antonio | Texas | United States | 78229 |
| 273 | Scott and White Memorial Hospital | Temple | Texas | United States | 76508 |
| 274 | Primary Children's Hospital | Salt Lake City | Utah | United States | 84113 |
| 275 | Central Vermont Medical Center/National Life Cancer Treatment | Berlin | Vermont | United States | 05602 |
| 276 | University of Vermont Medical Center | Burlington | Vermont | United States | 05401 |
| 277 | University of Vermont and State Agricultural College | Burlington | Vermont | United States | 05405 |
| 278 | Inova Fairfax Hospital | Falls Church | Virginia | United States | 22042 |
| 279 | Children's Hospital of The King's Daughters | Norfolk | Virginia | United States | 23507 |
| 280 | Naval Medical Center - Portsmouth | Portsmouth | Virginia | United States | 23708-2197 |
| 281 | Virginia Commonwealth University/Massey Cancer Center | Richmond | Virginia | United States | 23298 |
| 282 | Carilion Children's | Roanoke | Virginia | United States | 24014 |
| 283 | Harrison HealthPartners Hematology and Oncology-Bremerton | Bremerton | Washington | United States | 98310 |
| 284 | Harrison Medical Center | Bremerton | Washington | United States | 98310 |
| 285 | Highline Medical Center-Main Campus | Burien | Washington | United States | 98166 |
| 286 | Saint Elizabeth Hospital | Enumclaw | Washington | United States | 98022 |
| 287 | Saint Francis Hospital | Federal Way | Washington | United States | 98003 |
| 288 | Saint Clare Hospital | Lakewood | Washington | United States | 98499 |
| 289 | Harrison HealthPartners Hematology and Oncology-Poulsbo | Poulsbo | Washington | United States | 98370 |
| 290 | Seattle Children's Hospital | Seattle | Washington | United States | 98105 |
| 291 | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington | United States | 99204 |
| 292 | Franciscan Research Center-Northwest Medical Plaza | Tacoma | Washington | United States | 98405 |
| 293 | Mary Bridge Children's Hospital and Health Center | Tacoma | Washington | United States | 98405 |
| 294 | Northwest Medical Specialties PLLC | Tacoma | Washington | United States | 98405 |
| 295 | Madigan Army Medical Center | Tacoma | Washington | United States | 98431 |
| 296 | West Virginia University Healthcare | Morgantown | West Virginia | United States | 26506 |
| 297 | Green Bay Oncology at Saint Vincent Hospital | Green Bay | Wisconsin | United States | 54301-3526 |
| 298 | Saint Vincent Hospital Cancer Center Green Bay | Green Bay | Wisconsin | United States | 54301 |
| 299 | Saint Vincent Hospital Cancer Center at Marinette | Marinette | Wisconsin | United States | 54143 |
| 300 | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin | United States | 54449 |
| 301 | Children's Hospital of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
| 302 | Alberta Children's Hospital | Calgary | Alberta | Canada | T3B 6A8 |
| 303 | University of Alberta Hospital | Edmonton | Alberta | Canada | T6G 2B7 |
| 304 | British Columbia Children's Hospital | Vancouver | British Columbia | Canada | V6H 3V4 |
| 305 | CancerCare Manitoba | Winnipeg | Manitoba | Canada | R3E 0V9 |
| 306 | Janeway Child Health Centre | Saint John's | Newfoundland and Labrador | Canada | A1B 3V6 |
| 307 | IWK Health Centre | Halifax | Nova Scotia | Canada | B3K 6R8 |
| 308 | McMaster Children's Hospital at Hamilton Health Sciences | Hamilton | Ontario | Canada | L8N 3Z5 |
| 309 | Kingston Health Sciences Centre | Kingston | Ontario | Canada | K7L 2V7 |
| 310 | Children's Hospital | London | Ontario | Canada | N6A 5W9 |
| 311 | Children's Hospital of Eastern Ontario | Ottawa | Ontario | Canada | K1H 8L1 |
| 312 | Hospital for Sick Children | Toronto | Ontario | Canada | M5G 1X8 |
| 313 | The Montreal Children's Hospital of the MUHC | Montreal | Quebec | Canada | H3H 1P3 |
| 314 | Centre Hospitalier Universitaire Sainte-Justine | Montreal | Quebec | Canada | H3T 1C5 |
| 315 | Centre Hospitalier Universitaire de Quebec | Quebec | Canada | G1V 4G2 | |
| 316 | San Jorge Children's Hospital | San Juan | Puerto Rico | 00912 | |
| 317 | University Pediatric Hospital | San Juan | Puerto Rico | 00926 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Steven G DuBois, Children's Oncology Group
Study Documents (Full-Text)
More Information
Publications
None provided.- NCI-2014-02380
- NCI-2014-02380
- AEWS1221
- s15-00442
- AEWS1221
- AEWS1221
- U10CA180886
- U10CA098543
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Period Title: Overall Study | ||
| STARTED | 157 | 155 |
| COMPLETED | 93 | 86 |
| NOT COMPLETED | 64 | 69 |
Baseline Characteristics
| Arm/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | Total |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Total of all reporting groups |
| Overall Participants | 157 | 155 | 312 |
| Age (Count of Participants) | |||
| <=18 years |
124
79%
|
123
79.4%
|
247
79.2%
|
| Between 18 and 65 years |
33
21%
|
32
20.6%
|
65
20.8%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Age (years) [Mean (Inter-Quartile Range) ] | |||
| Mean (Inter-Quartile Range) [years] |
14.89
|
15.16
|
15.03
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
71
45.2%
|
69
44.5%
|
140
44.9%
|
| Male |
86
54.8%
|
86
55.5%
|
172
55.1%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
28
17.8%
|
23
14.8%
|
51
16.3%
|
| Not Hispanic or Latino |
113
72%
|
116
74.8%
|
229
73.4%
|
| Unknown or Not Reported |
16
10.2%
|
16
10.3%
|
32
10.3%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
1
0.6%
|
0
0%
|
1
0.3%
|
| Asian |
4
2.5%
|
4
2.6%
|
8
2.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
2
1.3%
|
2
0.6%
|
| Black or African American |
5
3.2%
|
3
1.9%
|
8
2.6%
|
| White |
128
81.5%
|
125
80.6%
|
253
81.1%
|
| More than one race |
2
1.3%
|
0
0%
|
2
0.6%
|
| Unknown or Not Reported |
17
10.8%
|
21
13.5%
|
38
12.2%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
144
91.7%
|
142
91.6%
|
286
91.7%
|
| Canada |
10
6.4%
|
11
7.1%
|
21
6.7%
|
| China |
0
0%
|
1
0.6%
|
1
0.3%
|
| Guatemala |
1
0.6%
|
0
0%
|
1
0.3%
|
| Puerto Rico |
2
1.3%
|
1
0.6%
|
3
1%
|
Outcome Measures
| Title | Event-free Survival |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only eligible patients are considered in the calculation of this outcome measure. |
| Arm/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 148 | 150 |
| Number (95% Confidence Interval) [percent probability of participants] |
30.88
19.7%
|
30.4
19.6%
|
| Title | Overall Survival |
|---|---|
| Description | Time from study enrollment to death or last patient contact. |
| Time Frame | 5 years after enrollment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only eligible patients are considered in the calculation of this outcome measure. |
| Arm/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 148 | 150 |
| Number (95% Confidence Interval) [Percent Probability] |
44.93
|
48.19
|
| Title | Frequency of Toxicity-events |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 145 | 150 |
| Measure Reporting Periods | 527 | 576 |
| Number [Reporting Periods] |
10
|
27
|
| Title | Serum IGF Pathway Component and Tissue Protein, Deoxyribonucleic Acid (DNA), and Ribonucleic Acid Markers |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Tumor Cell Surface IGF-1R Expression |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Germline Polymorphisms in EGFR |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | EWS Translocation |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Circulating Tumor DNA (ctDNA) Testing |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Serial Genomic Profiling |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Occurrence of Sinusoidal Obstructive Disease (SOS) Associated With the Addition of Ganitumab to VDC/IE |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Frequency of Resolution of Bone Marrow Metastases |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Frequency of Toxicity Events During Ganitumab Maintenance |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Trough Levels of Serum Ganitumab |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Proportion of Patients Who Successfully Receive Planned Stereotactic Body Radiotherapy (SBRT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Adverse Events monitored up to 358 days from study enrollment, All-Cause Mortality monitored up to 5 years | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | 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. | |||
| Arm/Group Title | Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | ||
| Arm/Group Description | 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 | 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 | ||
All Cause Mortality |
||||
| Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 61/145 (42.1%) | 67/150 (44.7%) | ||
Serious Adverse Events |
||||
| Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/145 (2.1%) | 45/150 (30%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 0/145 (0%) | 0 | 6/150 (4%) | 6 |
| Cardiac disorders | ||||
| Left ventricular systolic dysfunction | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Sinus tachycardia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 1/145 (0.7%) | 1 | 3/150 (2%) | 3 |
| Colitis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Colonic perforation | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Constipation | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Dysphagia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Esophagitis | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Gastrointestinal disorders - Other, specify | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Ileus | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Mucositis oral | 1/145 (0.7%) | 1 | 6/150 (4%) | 6 |
| Nausea | 0/145 (0%) | 0 | 9/150 (6%) | 9 |
| Oral pain | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Rectal fistula | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Rectal mucositis | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Typhlitis | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Vomiting | 0/145 (0%) | 0 | 6/150 (4%) | 6 |
| General disorders | ||||
| Fever | 1/145 (0.7%) | 1 | 2/150 (1.3%) | 2 |
| Immune system disorders | ||||
| Allergic reaction | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Anaphylaxis | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Infections and infestations | ||||
| Anorectal infection | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Appendicitis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Infections and infestations - Other, specify | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Sepsis | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Skin infection | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Fracture | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Investigations | ||||
| Alanine aminotransferase increased | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Aspartate aminotransferase increased | 0/145 (0%) | 0 | 3/150 (2%) | 3 |
| Ejection fraction decreased | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Lipase increased | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Lymphocyte count decreased | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Neutrophil count decreased | 0/145 (0%) | 0 | 4/150 (2.7%) | 4 |
| Platelet count decreased | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Weight loss | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| White blood cell decreased | 0/145 (0%) | 0 | 4/150 (2.7%) | 4 |
| Metabolism and nutrition disorders | ||||
| Anorexia | 0/145 (0%) | 0 | 8/150 (5.3%) | 8 |
| Dehydration | 0/145 (0%) | 0 | 3/150 (2%) | 3 |
| Hypoalbuminemia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hypocalcemia | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Hyponatremia | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Hypophosphatemia | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Bone pain | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Nervous system disorders | ||||
| Edema cerebral | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Encephalopathy | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Headache | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Memory impairment | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Neuralgia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Stroke | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Syncope | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Dyspnea | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Epistaxis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hypoxia | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Pneumonitis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Respiratory failure | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Wheezing | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Urticaria | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Vascular disorders | ||||
| Hypertension | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hypotension | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Thromboembolic event | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Regimen A (VDC/IE) | Regimen B (VDC/IE + Ganitumab) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 114/145 (78.6%) | 122/150 (81.3%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 3/145 (2.1%) | 3 | 7/150 (4.7%) | 7 |
| Febrile neutropenia | 38/145 (26.2%) | 38 | 50/150 (33.3%) | 50 |
| Leukocytosis | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Cardiac disorders | ||||
| Sinus tachycardia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Eye disorders | ||||
| Papilledema | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 2/145 (1.4%) | 2 | 3/150 (2%) | 3 |
| Anal fistula | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Anal pain | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Colitis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Constipation | 2/145 (1.4%) | 2 | 0/150 (0%) | 0 |
| Diarrhea | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Enterocolitis | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Gastrointestinal disorders - Other, specify | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hemorrhoids | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Mucositis oral | 6/145 (4.1%) | 6 | 9/150 (6%) | 9 |
| Nausea | 8/145 (5.5%) | 8 | 0/150 (0%) | 0 |
| Oral pain | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Pancreatitis | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Rectal mucositis | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Rectal pain | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Small intestinal obstruction | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Vomiting | 4/145 (2.8%) | 4 | 2/150 (1.3%) | 2 |
| General disorders | ||||
| Fever | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Infusion related reaction | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Pain | 3/145 (2.1%) | 3 | 2/150 (1.3%) | 2 |
| Immune system disorders | ||||
| Anaphylaxis | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Infections and infestations | ||||
| Abdominal infection | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Bladder infection | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Enterocolitis infectious | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Infections and infestations - Other, specify | 4/145 (2.8%) | 4 | 6/150 (4%) | 6 |
| Lymph gland infection | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Periorbital infection | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Pleural infection | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Sepsis | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Skin infection | 2/145 (1.4%) | 2 | 2/150 (1.3%) | 2 |
| Soft tissue infection | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Upper respiratory infection | 2/145 (1.4%) | 2 | 1/150 (0.7%) | 1 |
| Urinary tract infection | 5/145 (3.4%) | 5 | 3/150 (2%) | 3 |
| Vaginal infection | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Wound infection | 1/145 (0.7%) | 1 | 2/150 (1.3%) | 2 |
| Injury, poisoning and procedural complications | ||||
| Burn | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Investigations | ||||
| Alanine aminotransferase increased | 3/145 (2.1%) | 3 | 4/150 (2.7%) | 4 |
| Aspartate aminotransferase increased | 2/145 (1.4%) | 2 | 3/150 (2%) | 3 |
| Blood bilirubin increased | 2/145 (1.4%) | 2 | 1/150 (0.7%) | 1 |
| GGT increased | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Lymphocyte count decreased | 26/145 (17.9%) | 26 | 20/150 (13.3%) | 20 |
| Neutrophil count decreased | 91/145 (62.8%) | 91 | 92/150 (61.3%) | 92 |
| Platelet count decreased | 24/145 (16.6%) | 24 | 68/150 (45.3%) | 68 |
| Weight loss | 1/145 (0.7%) | 1 | 2/150 (1.3%) | 2 |
| White blood cell decreased | 82/145 (56.6%) | 82 | 85/150 (56.7%) | 85 |
| Metabolism and nutrition disorders | ||||
| Alkalosis | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Anorexia | 8/145 (5.5%) | 8 | 5/150 (3.3%) | 5 |
| Dehydration | 3/145 (2.1%) | 3 | 1/150 (0.7%) | 1 |
| Glucose intolerance | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hyperglycemia | 1/145 (0.7%) | 1 | 6/150 (4%) | 6 |
| Hypoalbuminemia | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Hypocalcemia | 2/145 (1.4%) | 2 | 0/150 (0%) | 0 |
| Hypoglycemia | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Hypokalemia | 6/145 (4.1%) | 6 | 5/150 (3.3%) | 5 |
| Hyponatremia | 4/145 (2.8%) | 4 | 2/150 (1.3%) | 2 |
| Hypophosphatemia | 4/145 (2.8%) | 4 | 2/150 (1.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Buttock pain | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Chest wall pain | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Joint range of motion decreased | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Musculoskeletal and connective tissue disorder - Other, specify | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Pain in extremity | 2/145 (1.4%) | 2 | 0/150 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Tumor pain | 2/145 (1.4%) | 2 | 2/150 (1.3%) | 2 |
| Nervous system disorders | ||||
| Headache | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Peripheral sensory neuropathy | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Somnolence | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Syncope | 2/145 (1.4%) | 2 | 2/150 (1.3%) | 2 |
| Psychiatric disorders | ||||
| Anxiety | 1/145 (0.7%) | 1 | 1/150 (0.7%) | 1 |
| Renal and urinary disorders | ||||
| Hematuria | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Bronchospasm | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Epistaxis | 0/145 (0%) | 0 | 3/150 (2%) | 3 |
| Hypoxia | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Pleural effusion | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Respiratory failure | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash acneiform | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Skin and subcutaneous tissue disorders - Other, specify | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Skin ulceration | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Surgical and medical procedures | ||||
| Surgical and medical procedures - Other, specify | 0/145 (0%) | 0 | 1/150 (0.7%) | 1 |
| Vascular disorders | ||||
| Hypertension | 0/145 (0%) | 0 | 2/150 (1.3%) | 2 |
| Hypotension | 1/145 (0.7%) | 1 | 0/150 (0%) | 0 |
| Thromboembolic event | 2/145 (1.4%) | 2 | 1/150 (0.7%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Results Reporting Coordinator |
|---|---|
| Organization | Children's Oncology Group |
| Phone | 16264470064 |
| resultsreportingcoordinator@childrensoncologygroup.org |
- NCI-2014-02380
- NCI-2014-02380
- AEWS1221
- s15-00442
- AEWS1221
- AEWS1221
- U10CA180886
- U10CA098543