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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01795430
First received: February 18, 2013
Last updated: February 11, 2014
Last verified: February 2014
  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: 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

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • 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 [ 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.


Secondary Outcome Measures:
  • 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: July 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 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.

Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: ifosfamide
Given IV
Other Names:
  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
Radiation: intensity-modulated radiation therapy
Undergo WB-MRI-guided IMRT
Other Name: IMRT
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
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:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: autologous bone marrow transplantation
Undergo autologous bone marrow transplant
Other Names:
  • ABMT
  • bone marrow transplantation, autologous
  • transplantation, autologous bone marrow

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 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.

  Eligibility

Ages Eligible for Study:   6 Months to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01795430

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Anna B. Pawlowska, MD    800-826-4673    apawlowska@coh.org   
Principal Investigator: Anna B. Pawlowska         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
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 11, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Sarcoma, Ewing's
Neuroectodermal Tumors, Primitive, Peripheral
Sarcoma
Osteosarcoma
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 July 28, 2014