Ewing Sarcoma of Bone, Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Conditions
Brief summary
This clinical trial is studying the side effects of combination chemotherapy and to see how well they work in treating patients with newly diagnosed localized Ewing sarcoma family of tumors. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different ways may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To assess the feasibility and safety of adding interval-compressed vincristine, topotecan hydrochloride, and cyclophosphamide to a treatment protocol utilizing interval compression of vincristine, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide in patients with localized Ewing sarcoma family of tumors. SECONDARY OBJECTIVES: I. To estimate the event-free survival in patients treated with this regimen. OUTLINE: This is a multicenter study. INDUCTION THERAPY (WEEKS 1-12): Patients receive vincristine IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11, and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 1 hour on days 1-5 in weeks 1 and 9 and on day 1 in weeks 5 and 11; ifosfamide IV over 1 hour on days 1-5 in weeks 3 and 7; etoposide IV over 1 hour on days 1-5 in weeks 3 and 7; and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 5 and 11. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning 24-36 hours after the last dose of chemotherapy and continuing for at least 7 days or until blood counts recover, whichever comes last. Filgrastim is discontinued at least 24 hours prior to the next course of chemotherapy. LOCAL CONTROL: Patients who respond to induction therapy may undergo surgery alone if the lesion can be resected with negative margins and with a reasonable functional result beginning in week 13. Following surgery, patients with unresectable lesions or inadequate margins may receive radiotherapy during week 15. Patients with bulky lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis; poor response to induction chemotherapy; or those in whom surgery would result in unacceptable functional results may receive radiotherapy alone in weeks 13-19. Patients with bulky lesions in difficult sites and who do not have a good clinical and radiographic response to induction therapy may receive radiotherapy to the primary site during weeks 13-19 followed by surgery of the involved site during week 25 after recovery from course 11 of chemotherapy. Patients with microscopic residual disease after planned pre-operative radiotherapy will receive additional radiotherapy. CONTINUATION THERAPY (WEEKS 15-36): Patients receive vincristine IV on day 1 in weeks 15, 16, 21-24, 27-30, 33, and 34; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 15, 21, and 29; cyclophosphamide IV over 1 hour on days 1-5 in weeks 15, 21 and 29 and on day 1 in weeks 23, 27, and 33; ifosfamide IV over 1 hour on days 1-5 in weeks 17, 19, 25, 31, and 35; etoposide IV over 1 hour on days 1-5 in weeks 17, 19, 25, 31, and 35; and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 of weeks 23, 27, and 33. Patients also receive G-CSF SC as in induction therapy. After completion of study treatment, patients are followed for 10 years.
Interventions
OTHERradiation therapy
Undergo radiation therapy
OTHERtherapeutic conventional surgery
Undergo surgery
DRUGetoposide
Given IV
DRUGifosfamide
Given IV
DRUGdoxorubicin hydrochloride
Given IV
DRUGcyclophosphamide
Given IV
DRUGvincristine sulfate
Given IV
DRUGtopotecan hydrochloride
Given IV
BIOLOGICALfilgrastim
Given SC
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of extracranial Ewing sarcoma or peripheral primitive neuroectodermal tumor of bone or soft tissue: * Newly diagnosed disease * Disease confirmed by biopsy only with no attempt at complete or partial resection * Unplanned excision allowed provided adequate imaging was obtained prior to surgery and incompletely resected disease is controlled by local therapy * No esthesioneuroblastoma * Localized disease, including any of the following sites: * Chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology, or ipsilateral pleural based secondary tumor nodules; * No contralateral pleural effusions or pleural nodules * Regional lymph nodes that are clinically suspicious or confirmed by biopsy * No distant lymph node metastases * Extra-dural tumors arising in the bony skull * No tumors arising in the intra-dural soft tissue or the intra-dural region of the spine * No evidence of metastatic disease, defined as any of the following: * Lesions that are discontinuous from the primary tumor * Lesions that are not regional lymph nodes * Lesions that do not share a body cavity with the primary tumor * No evidence by CT scan of metastatic lung disease, defined as any of the following: * One pulmonary nodule \> 1 cm in diameter or more than one nodule \> 0.5 cm diameter * Pulmonary nodules that are resected and are not found to be metastatic Ewing sarcoma are allowed * Biopsy proven solitary nodules measuring 0.5 to 1.0 cm or multiple nodules measuring 0.3 to 0.5 cm * Solitary nodules measuring \< 0.5 cm or multiple nodules measuring \< 0.3 cm are allowed unless biopsy proven to be metastatic (biopsy is not required) * Karnofsky performance status (PS) 0-2 (\>= 16 years old) OR Lansky PS 0-2 (\< 16 years old) * Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows: * 1 month to \< 6 months old (males and females 0.4 mg/dL) * 6 months to \< 1 year old (males and females 0.5 mg/dL) * 1 to \< 2 years old (males and females 0.6 mg/dL) * 2 to \< 6 years old (males and females 0.8 mg/dL) * 6 to \< 10 years old (males and females 1.0 mg/dL) * 10 to \< 13 years old (males and females 1.2 mg/dL) * 13 to \< 16 years old (males 1.5 mg/dL and females 1.4 mg/dL) * \>= 16 years old (males 1.7 mg/dL and females 1.4 mg/dL) * AST or ALT \< 2.5 times ULN for age * Total bilirubin =\< 1.5 times upper limit of normal (ULN) for age * Shortening fraction of \>= 27% by ECHO or ejection fraction of \>= 50% by radionuclide angiogram (MUGA) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No prior chemotherapy or radiotherapy * No concurrent pegfilgrastim (Neulasta) or sargramostim (GM-CSF) * No other concurrent cancer chemotherapy or immunomodulating agents, including steroids, unless used as an antiemetic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Death | Length of protocol therapy (up to 37 weeks) plus 30 days | Incidence of death from complications of therapy while the patient is on protocol therapy or within one month of terminating protocol therapy |
| Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Enrollment to Week 12 | Enrollment to week 12 | The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks. |
| Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 13 to Week 22 | Week 13 to week 22 | The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks. |
| Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 23 to Week 28 | Week 23 to week 28 | The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks. |
| Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 29 to Week 37 | Week 29 to week 37 | The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | From enrollment to event or 10 years from enrollment, whichever occurs first | Disease progression, occurrence of a second malignant neoplasm (SMN)or death will be considered an analytic event. In all other cases, the patient will be considered censored at last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Combination Chemotherapy) See Detailed Description
radiation therapy: Undergo radiation therapy
therapeutic conventional surgery: Undergo surgery
etoposide: Given IV
ifosfamide: Given IV
doxorubicin hydrochloride: Given IV
cyclophosphamide: Given IV
vincristine sulfate: Given IV
topotecan hydrochloride: Given IV
filgrastim: Given SC | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Combination Chemotherapy) |
|---|---|
| Age, Continuous | 11 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment Australia | 1 participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 35 |
| serious Total, serious adverse events | 2 / 35 |
Outcome results
Primary
Incidence of Death
Incidence of death from complications of therapy while the patient is on protocol therapy or within one month of terminating protocol therapy
Time frame: Length of protocol therapy (up to 37 weeks) plus 30 days
Population: Any patient who receives at least one cycle of protocol therapy, or who dies as a result of complications of therapy prior to completing one cycle of therapy will be evaluable for this outcome
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Combination Chemotherapy) | Incidence of Death | 0 participants |
Primary
Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Enrollment to Week 12
The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks.
Time frame: Enrollment to week 12
Population: Any patient who receives at least one cycle of protocol therapy, or who is removed from protocol therapy partly or solely because of a dose-limiting toxicity will be evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Combination Chemotherapy) | Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Enrollment to Week 12 | 12 participants |
Primary
Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 13 to Week 22
The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks.
Time frame: Week 13 to week 22
Population: One patient was not evaluated for dose-limiting toxicity during weeks 13-22 because patient did not complete that segment of protocol therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Combination Chemotherapy) | Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 13 to Week 22 | 9 participants |
Primary
Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 23 to Week 28
The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks.
Time frame: Week 23 to week 28
Population: One patient was not evaluated for DLT during weeks 23-28 because the patient did not complete that segment of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Combination Chemotherapy) | Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 23 to Week 28 | 9 participants |
Primary
Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 29 to Week 37
The incidence rate of DLT while on protocol therapy where DLT is defined as (1) Grade 3 or greater nonhematological adverse event that is possibly, probably, or likely related to therapy with the specific exception of Grade 3 or greater nausea or vomiting controlled by standard supportive care measures, Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE that delays the administration of therapy at least 2 weeks.
Time frame: Week 29 to week 37
Population: Two patients were not evaluated for DLT during weeks 29-37 because those patients did not complete that segment of protocol therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Combination Chemotherapy) | Incidence Rate (Number of Participants) of Dose-limiting Toxicity (DLT) - Week 29 to Week 37 | 14 participants |
Secondary
Event Free Survival
Disease progression, occurrence of a second malignant neoplasm (SMN)or death will be considered an analytic event. In all other cases, the patient will be considered censored at last contact.
Time frame: From enrollment to event or 10 years from enrollment, whichever occurs first