Whole-Body Radiation Therapy, Systemic Chemotherapy, and High-Dose Chemotherapy Followed By Stem Cell Rescue in Treating Patients With Poor-Risk Ewing Sarcoma

Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Clinical Trial

Official title:

A Pilot Study of 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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01795430
• Other study ID #: 12391
• Secondary ID: NCI-2013-00439
• Status: Withdrawn
• Phase: N/A
• First received: February 18, 2013
• Last updated: January 7, 2015
• Start date: July 2013

Study information

• Verified date: January 2015
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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

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 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 over 2 hours every 6 hours on days -8 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 40 Years

Eligibility

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

• Greater than 2 week period of recovery from prior modality used to control primary or recurrent site

• 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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)
• Ewing Sarcoma of Bone
• Extraosseous Ewing Sarcoma
• Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroectodermal Tumors, Primitive, Peripheral
• Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
• Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Sarcoma
• Sarcoma, Ewing
• Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Intervention

Drug:
• etoposide
Given IV
• ifosfamide
Given IV

Radiation:
• intensity-modulated radiation therapy
Undergo WB-MRI-guided IMRT

Drug:
• topotecan hydrochloride
Given IV
• busulfan
Given IV
• melphalan
Given IV

Procedure:
• autologous hematopoietic stem cell transplantation
Undergo autologous peripheral blood stem cell or bone marrow transplant
• peripheral blood stem cell transplantation
Undergo autologous peripheral blood stem cell transplant
• autologous bone marrow transplantation
Undergo autologous bone marrow transplant

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients who experience grade 4-5 non-hematologic toxicities assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	Toxicities will be summarized as type, severity, date of onset, duration, reversibility, and attribution.	Up to day 100 of Block II	Yes
Secondary	Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST)	Objective tumor response for all patients will be summarized, including the number and percent responding.	Up to 5 years	No
Secondary	Progression-free survival (PFS)	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.	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	No
Secondary	Overall survival (OS)	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.	Time from stem cell infusion to death from any cause, assessed up to 5 years	No
Secondary	Non-relapse mortality (NRM)	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.	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	No