Whole-Body Radiation Therapy, Systemic Chemotherapy, and High-Dose Chemotherapy Followed By Stem Cell Rescue in Treating Patients With Poor-Risk Ewing Sarcoma
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Purpose
This pilot clinical trial studies whole-body radiation therapy, systemic chemotherapy, and high-dose chemotherapy followed by stem cell rescue in treating patients with poor-risk Ewing sarcoma. Giving chemotherapy and radiation therapy before a peripheral blood stem cell or bone marrow transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is given to prepare the bone marrow for stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy
| Condition | Intervention |
|---|---|
|
Adult Supratentorial Primitive Neuroectodermal Tumor (PNET) Ewing Sarcoma of Bone Extraosseous Ewing Sarcoma Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor |
Drug: etoposide Drug: ifosfamide Radiation: intensity-modulated radiation therapy Drug: topotecan hydrochloride Drug: busulfan Drug: melphalan Procedure: autologous hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Procedure: autologous bone marrow transplantation |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Whole-body MRI-guided Intensity Modulated Radiation Therapy Combined With Systemic Chemotherapy Followed by High-Dose Chemotherapy With Busulfan, Melphalan and Topotecan and Stem Cell Rescue in Patients With Poor Risk Ewing's Sarcoma |
- Observed toxicities assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to day 100 of Block II ] [ Designated as safety issue: Yes ]Toxicities will be summarized as type, severity, date of onset, duration, reversibility, and attribution.
- Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Objective tumor response for all patients will be summarized, including the number and percent responding.
- Progression-free survival (PFS) [ Time Frame: Time from stem cell infusion to the first observation of disease progression or death from any cause, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]PFS will be estimated using the Kaplan-Meier product-limit method; 95% confidence intervals (CIs) will be calculated using the logit transformation and the Greenwood variance estimate.
- Overall survival (OS) [ Time Frame: Time from stem cell infusion to death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]OS will be estimated using the Kaplan-Meier product-limit method; 95% confidence intervals (CIs) will be calculated using the logit transformation and the Greenwood variance estimate.
- Non-relapse mortality (NRM) [ Time Frame: Time from stem cell infusion to death event where the cause of death is not attributable to the underlying disease, assessed up to 5 years ] [ Designated as safety issue: No ]Cumulative relapse incidence will be estimated treating non-relapse related death events as competing risks and, conversely, NRM will be calculated controlling for relapse as a competing risk. Cumulative incidence of NRM and relapse-related mortality will be calculated using the method of Goole et al. Cumulative incidence differences will be assessed by Gray's test.
| Estimated Enrollment: | 15 |
| Study Start Date: | March 2013 |
| Estimated Primary Completion Date: | March 2018 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (radiation therapy/chemotherapy, stem cell infusion)
BLOCK I: Patients receive etoposide IV over 1-2 hours and ifosfamide IV over 1 hour on days 1-5. Patients also undergo WB-MRI-guided intensity-modulated radiation therapy BID, 5 days a week, for approximately 4 weeks. Patients may also undergo 4 fractions of SRT QOD, 3-8 fractions of SBRT QOD, or 10 fractions of 3D RT daily to sites of metastatic disease. BLOCK II: Patients receive high-dose chemotherapy comprising topotecan hydrochloride IV continuously over 24 hours on days -8 to -4, busulfan IV every 6 hours on days -7 to -4, and melphalan IV over 30 minutes on days -3 and -2. Patients undergo autologous peripheral blood or bone marrow stem cell infusion on day 0. |
Drug: etoposide
Given IV
Other Names:
Drug: ifosfamide
Given IV
Other Names:
Radiation: intensity-modulated radiation therapy
Undergo WB-MRI-guided IMRT
Other Name: IMRT
Drug: topotecan hydrochloride
Given IV
Other Names:
Drug: busulfan
Given IV
Other Names:
Drug: melphalan
Given IV
Other Names:
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous peripheral blood stem cell or bone marrow transplant
Procedure: peripheral blood stem cell transplantation
Undergo autologous peripheral blood stem cell transplant
Other Names:
Procedure: autologous bone marrow transplantation
Undergo autologous bone marrow transplant
Other Names:
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To assess the safety and feasibility of whole-body magnetic resonance imaging (WB-MRI)-guided intensity modulated radiation therapy delivered concurrently with systemic chemotherapy to sites of metastatic disease in patients with relapsed, refractory and/or poor risk Ewing sarcoma.
II. To assess the safety and feasibility of a novel consolidation regimen consisting of busulfan, melphalan and topotecan (topotecan hydrochloride) followed by autologous stem cell rescue, to be administered immediately after completion of radiation therapy in patients with relapsed, refractory and/or poor risk Ewing sarcoma.
SECONDARY OBJECTIVES:
I. To characterize the timing of myeloid and platelet engraftment. II. To estimate the overall and progression free survival probabilities. III. To estimate the cumulative incidence of relapse/progression and non-relapse related mortality.
IV. To report the overall response rate (overall response rate [ORR]: complete response [CR]+partial response [PR]) and response duration.
V. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population treated with standard high-dose therapy [HDT] for high-risk, advanced Ewing sarcoma.
VI. To descriptively compare the diagnostic imaging results (number and site of bone metastases) of whole-body MR imaging to those obtained by skeletal scintigraphy.
OUTLINE:
BLOCK I: Patients receive etoposide intravenously (IV) over 1-2 hours and ifosfamide IV over 1 hour on days 1-5. Patients also undergo WB-MRI-guided intensity-modulated radiation therapy twice daily (BID), 5 days a week, for approximately 4 weeks. Patients may also undergo 4 fractions of stereotactic radiation therapy (SRT) every other day (QOD), 3-8 fractions of stereotactic body radiation therapy (SBRT) QOD, or 10 fractions of 3-dimensional radiation therapy (3D RT) daily to sites of metastatic disease.
BLOCK II: Patients receive high-dose chemotherapy comprising topotecan hydrochloride IV continuously over 24 hours on days -8 to -4, busulfan IV every 6 hours on days -7 to -4, and melphalan IV over 30 minutes on days -3 and -2. Patients undergo autologous peripheral blood or bone marrow stem cell infusion on day 0.
After the stem cell infusion, patients are followed up for up to 5 years.
Eligibility| Ages Eligible for Study: | 6 Months to 40 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with relapsed Ewing's sarcoma or primitive neuroectodermal tumor (PNET) with bony/soft tissue metastasis who achieved at least partial response (PR) to chemotherapy, surgery or radiotherapy
- Newly diagnosed patients with metastatic disease to the bones: patients with metastatic Ewing's or metastatic PNET who achieved at least partial response (PR) to chemotherapy, surgery or radiotherapy are eligible
- Ewing's sarcoma/PNET histology confirmed by Anatomic Pathology Department; histological confirmation of relapse is highly recommended but not mandatory
- Patients must have documented at least partial response (PR) to previous therapy regimens; previous modalities may include surgery, chemotherapy, or radiation therapy; radiation must not include lung fields; only patients in CR or PR at the primary site will be eligible
- Patients must have metastatic/recurrent disease identified by WB-MRI at the time of study entry; intensity-modulated radiation therapy (IMRT) can be delivered per protocol guidelines to at least one but not more than five primary/metastatic sites
- Patients must have Karnofsky performance status > 60% OR Lansky performance status > 50% for patients younger than 16 years old
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
- Adequate number of autologous stem cells collected and cryopreserved prior to starting the study treatment
- Creatinine clearance (12 or 24 hour urine collection) or glomerular filtration rate (GFR) > 60 ml/min/1.73 m^2
- Ejection fraction > 50% by echocardiogram or multiple gated acquisition (MUGA)
- Bilirubin < 2 x upper limit of normal
- Serum glutamic oxalo-acetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 5 x upper limit of normal
- Platelet count > 50,000/ul
- Absolute granulocyte count >= 750/ul
- Forced expiratory volume in one second (FEV1) > 2 liters adults (older than 16 years)
- Room air arterial oxygen pressure (PaO2) > 70 mm Hg adults (older than 16 years)
- Room air partial pressure of carbon dioxide (PaCO2) < 42 mm Hg adults (older than 16 years)
- Diffusion capacity of carbon monoxide (DLCO) > 50% predicted
- If unable to cooperate with pulmonary function testing due to young age, then pulse oximetry >= 94% children (younger than 16 years)
- Pretreatment tests must have been performed within 4 weeks prior to initiation of protocol treatment
- No other medical and/or psychosocial problems which, in the opinion of the primary physician or principal investigator, would place the patient at unacceptable risk from this regimen
- All subjects or their legal guardians must have the ability to understand and the willingness to sign a written informed consent
Exclusion Criteria:
- Patients should not have any uncontrolled illness including ongoing or active infection
- Patients may not be receiving any other investigational agents, concurrent biological agents, or chemotherapy
- Patients must not have received prior chemotherapy or radiation within 2 weeks before study enrollment, and those who have not recovered from the adverse events due to agents administered more than 2 weeks earlier are excluded
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this study
- Patients with other active malignancies are ineligible for this study
- Patients with prior treatment with myeloablative therapy are excluded
- Karnofsky performance status < 60% or Lansky performance status < 50% for patients younger than 16 years old
- Patients who require irradiation to more than 5 disease sites are excluded
- Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
Contacts and Locations| United States, California | |
| City of Hope Medical Center | Not yet recruiting |
| Duarte, California, United States, 91010 | |
| Contact: Anna B. Pawlowska, MD 800-826-4673 apawlowska@coh.org | |
| Principal Investigator: Anna B. Pawlowska | |
| Principal Investigator: | Anna Pawlowska | City of Hope Medical Center |
More Information
No publications provided
| Responsible Party: | City of Hope Medical Center |
| ClinicalTrials.gov Identifier: | NCT01795430 History of Changes |
| Other Study ID Numbers: | 12391, NCI-2013-00439 |
| Study First Received: | February 18, 2013 |
| Last Updated: | February 18, 2013 |
| Health Authority: | United States: Federal Government |
Additional relevant MeSH terms:
|
Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Sarcoma, Ewing's Neuroectodermal Tumors, Primitive, Peripheral Sarcoma Osteosarcoma Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial Neoplasms, Glandular and Epithelial Neoplasms, Bone Tissue Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue |
Busulfan Melphalan Ifosfamide Isophosphamide mustard Etoposide phosphate Etoposide Topotecan Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |
ClinicalTrials.gov processed this record on May 19, 2013