Stem Cell Transplantation in Patients With High-Risk and Recurrent Pediatric Sarcomas

NCT00043979 | Completed Phase 2 Results

• 2 other identifiers: 02025902-C-0259
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine the safety and effectiveness of stem cell transplantation for treating patients with sarcomas (tumors of the bone, nerves, or soft tissue). Stem cells are immature cells in the bone marrow and blood stream that develop into blood cells. Stem cells transplanted from a healthy donor travel to the patient's bone marrow and begin producing normal cells. In patients with certain cancers, such as leukemia and lymphoma, the donor's immune cells attack the patient's cancer cells in what is called a "graft-versus-tumor" effect, contributing to cure of the disease. This study will determine whether this treatment can be used successfully to treat patients with sarcomas. Patients between 4 and 35 years of age with a sarcoma that has spread from the primary site or cannot be removed surgically, and for whom effective treatment is not available, may be eligible for this study. Candidates must have been diagnosed by the age of 30 at the time of enrollment. They must have a matched donor (usually a sibling). Participants undergo the following procedures: Donors: Stem cells are collected from the donor. To do this, the hormone granulocyte colony stimulating factor (G-CSF) is injected under the skin for several days to move stem cells out of the bone marrow into the bloodstream. Then, the cells are collected by apheresis. In this procedure the blood is drawn through a needle placed in one arm and pumped into a machine where the stem cells are separated out and removed. The rest of the blood is returned to the donor through a needle in the other arm. Patients: For patients who do not already have a central venous catheter (plastic tube), one is placed into a major vein. This tube can stay in the body the entire treatment period for giving medications, transfusing blood, , withdrawing blood samples, and delivering the donated stem cells. Before the transplant procedure, patients receive from one to three cycles of "induction" chemotherapy, with each cycle consisting of 5 days of fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone followed by at least a 17-day rest period. All the drugs are infused through the catheter except prednisone, which is taken by mouth. After the induction therapy, the patient is admitted to the hospital for 5 days of chemotherapy with high doses of cyclophosphamide, melphalan, and fludarabine. Two days later, the stem cells are infused. The anticipated hospital stay is about 3 weeks, but may be longer if complications arise. Patients are discharged when their white cell count is near normal, they have no fever or infection, they can take sufficient food and fluids by mouth, and they have no signs of serious graft-versus-host disease (GVHD)-a condition in which the donor's cells "see" the patient's cells as foreign and mount an immune response against them. After hospital discharge, patients are followed in the clinic at least once or twice weekly for a medical history, physical exam, and blood tests for 100 days. They receive medications to prevent infection and GVHD and, if needed, blood transfusions. If GVHD has not developed by about 120 days post transplant, patients receive additional white cells to boost the immune response. After 100 days, follow-up visits may be less frequent. Follow-up continues for at least 5 years. During the course of the study, patients undergo repeated medical evaluations, including blood tests and radiology studies, to check on the cancer and on any treatment side effects. On four occasions, white blood cells may be collected through apheresis to see if immune responses can be generated against the sarcomas treated in this study. Positron emission tomography (PET) scans may be done on five occasions. This test uses a radioactive material to produce images useful in detecting primary tumors and cancer that has spread.

Conditions

Sarcoma

Keywords

Ewing's Sarcoma; Rhabdomyosarcoma; Desmoplastic Small Round Cell Tumor; Sarcoma; Ewing Sarcoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Engraftment

  Engraftment is defined as rapid conversion to complete donor chimerism and is assessed by blood counts and chimerism, \>95% donor engraftment at day 100 in \>75% of patients.

  100 days

• Toxicity

  Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

  16.5 months

Secondary Outcomes (10)

• Number of Participants With Acute and Chronic GVHD

  up to 5 years or death

• Median Time to Reach Absolute Neutrophil Count of 500/mm(3)

  up to 12 days

• Median Time to Reach a Platelet Count of 50,000/mm(3)

  up to 43 days

• Early Post Transplantation Relapse

  up to 300 days

• Median Progression Free Survival

  up to 77 months

Other Outcomes (2)

• Number of Participants Who Experienced Graft Versus Tumor Effect (GVT)

  up to day 100

• Post-Hematopoietic Stem Cell Transplant (HSCT) Radiotherapy

  up to 6 cycles or 168 days

Study Arms (2)

Arm 1- Sibling Donors

EXPERIMENTAL

Donors (n = 30) were matched first degree relatives who were eligible to donate peripheral blood stem cells.

Drug: Filgrastim; Procedure: Peripheral Blood Stem Cell donation

Arm 2 - Recipients

EXPERIMENTAL

Recipients (n=30) were enrolled to receive peripheral blood stem cells (PBSC) and receive either cyclosporine or tacrolimus and sirolimus for graft versus host disease (GVHD) prophylaxis.

Drug: F-18 Fluorodeoxyglucose; Biological: therapeutic allogeneic lymphocytes; Drug: cyclophosphamide; Drug: cyclosporine; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: fludarabine phosphate; Drug: melphalan; Drug: prednisone; Drug: sirolimus; Drug: tacrolimus; Drug: vincristine sulfate; Procedure: peripheral blood stem cell transplantation; Drug: Filgrastim

Interventions

F-18 Fluorodeoxyglucose DRUG

Also known as: FDG

Arm 2 - Recipients

therapeutic allogeneic lymphocytes BIOLOGICAL

Lymphocyte cells are collected from a healthy donor by apheresis and infused into the patient with a central venous catheter.

Arm 2 - Recipients

cyclophosphamide DRUG

Induction - 750 mg/m\^2 intravenous (IV) infusion over 30 minutes x 1 dose. Day 5. Transplant - 1200 mg/m\^2 per day IV infusion over 2 hours daily for 4 days; days -6, -5, -4, -3.

Also known as: Cytoxan

Arm 2 - Recipients

cyclosporine DRUG

6 mg/kg per dose orally every other day (no day 9 dose).

Also known as: Sandimmune

Arm 2 - Recipients

doxorubicin hydrochloride DRUG

Induction - 10 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.

Also known as: Adriamycin

Arm 2 - Recipients

etoposide DRUG

50 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days. Days 1, 2, 3, 4.

Also known as: Vepesid

Arm 2 - Recipients

fludarabine phosphate DRUG

Induction - 25 mg/m\^2 per day intravenous (IV) infusion over 30 minutes daily for 3 days. Days 1, 2, 3. Transplant - 30 mg/m\^2 per day IV infusion over 30 minutes daily for 4 days; days -6, -5, -4, -3.

Also known as: Fludara

Arm 2 - Recipients

melphalan DRUG

Transplant - 100 mg/m\^2 per day intravenous (IV) infusion over 15 minutes for 1 day; day -2.

Also known as: Alkeran

Arm 2 - Recipients

prednisone DRUG

Induction - 60 mg/m\^2 per day in 2-4 divided doses by mouth daily for 5 days; days 1, 2, 3, 4, 5.

Also known as: Deltasone

Arm 2 - Recipients

sirolimus DRUG

Initiated on day +3. Patients \>40kg, the initial dose will be 2 mg every 24 hours orally. Patients \<40 kg, the initial dose will be 1 mg/m\^2.

Also known as: Rapamune

Arm 2 - Recipients

tacrolimus DRUG

Day -1 at least 24 hours before the stem cell infusion at a dose of 0.03 mg/kg/day as a continuous infusion. Twelve hours later oral dose initiated at a dose of 0.1-0.15 mg/kg/day in two divided doses every 12 hours.

Also known as: Prograf

Arm 2 - Recipients

vincristine sulfate DRUG

Induction - 0.4 mg/m\^2 per day continuous intravenous (IV) infusion over 24 hours daily for 4 days; 1, 2, 3, 4.

Also known as: Oncovin

Arm 2 - Recipients

peripheral blood stem cell transplantation PROCEDURE

Stem cells from a healthy donor are collected and transplanted into the patient using a central venous catheter.

Also known as: PBSCT

Arm 2 - Recipients

Filgrastim DRUG

Arm 1- Sibling Donors; Arm 2 - Recipients

Peripheral Blood Stem Cell donation PROCEDURE

Arm 1- Sibling Donors

Eligibility Criteria

• Age: 5 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• The following diagnoses will be considered:
• Patients with Ewing's sarcoma family of tumors, or alveolar
• rhabdomyosarcoma in one of the following categories:
• Patients who present at the time of initial diagnosis with bone or bone marrow metastases may be enrolled after completion of standard front-line therapy. Standard front line therapy for alveolar rhabdomyosarcoma should include vincristine and cyclophosphamide, plus actinomycin D and/or adriamycin. For patients with Ewing's sarcoma, standard front line therapy should include vincristine, cyclophosphamide, adriamycin, ifosfamide and etoposide.
• Patients with recurrence of tumor at any site less than one year after completing standard front-line therapy or with a second or subsequent recurrence at any time after completing standard front-line therapy.
• Patients with progression or persistence of disease while receiving standard front-line chemotherapy who cannot achieve a complete response (CR) with local treatment modalities.
• The following patients with desmoplastic small round cell tumor are eligible after receiving front line standard therapy, which is defined as a regimen containing at least vincristine, cyclophosphamide, and adriamycin:
• unresectable disease
• metastatic tumor (abdominal and extra-abdominal disease)
• progressive or persistent while receiving standard therapy
• recurrence within one year of completing therapy
• Patients without evaluable tumor at the time of enrollment are eligible
• Patients who have previously received high-dose chemotherapy with autologous stem cell rescue are eligible for this trial.
• Patient age 5-35 at enrollment.
• Availability of a 5 or 6 antigen human leukocyte antigen (HLA)-matched first-degree relative donor (single HLA-A or B mismatch allowed). Genotypically identical twins may serve as stem cell donors. Genotypic identity must be confirmed by restrictive fragment length polymorphism (RFLP) analysis.

You may not qualify if:

• Uncontrolled fungal infection.
• History of untreated CNS tumor involvement. Extradural masses which have not invaded the brain parenchyma (as is commonly observed in Ewing's sarcoma family of tumors) or parameningeal tumors (as is commonly observed in rhabdomyosarcoma) without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous central nervous system (CNS) tumor involvement that has been treated and has been stable for at least 6 weeks are eligible.
• Lactating or pregnant females.
• Human immunodeficiency virus (HIV) positive (due to unacceptable risk following allogeneic transplantation).
• Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with elevated liver transaminases. All patients with chronic active hepatitis (including those on treatment) are ineligible.
• High risk of inability to comply with transplant protocol, or inability to give appropriate informed consent in the estimation of the principal investigator (PI), social work, or the stem cell transplant team.
• Fanconi Anemia
• History of medical illness which poses a risk to donation in the estimation of the PI or the Department of Transfusion Medicine physician including, but not limited to stroke, hypertension that is not controlled with medication, or heart disease. Individuals with symptomatic angina or a history of coronary bypass grafting or angioplasty will not be eligible.
• History of congenital hematologic, immunologic, oncologic or metabolic disorder, which poses a prohibitive risk to the recipient in the estimation of the PI.
• Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000/micro l).
• Lactating or pregnant females. Donors of childbearing potential must use an effective method of contraception during the time they are receiving growth colony stimulating factor (G-CSF). The effects of cytokine administration on a fetus are unknown and may be potentially harmful. The effects upon breast milk are also unknown and may potentially be harmful to the infant.
• Human immunodeficiency virus (HIV)-positive, hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive. Donors are providing an allogeneic blood product and there is the potential risk of transmitting these viral illnesses to the recipient.
• High risk of inability to comply with transplant protocol.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Dunst J, Sauer R, Burgers JM, Hawliczek R, Kurten R, Winkelmann W, Salzer-Kuntschik M, Muschenich M, Jurgens H. Radiation therapy as local treatment in Ewing's sarcoma. Results of the Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86. Cancer. 1991 Jun 1;67(11):2818-25. doi: 10.1002/1097-0142(19910601)67:113.0.co;2-y.

  PMID: 2025847 BACKGROUND

• Demeocq F, Oberlin O, Benz-Lemoine E, Boilletot A, Gentet JC, Zucker JM, Behar C, Poutard P, Olive D, Brunat-Mentigny M, et al. Initial chemotherapy including ifosfamide in the management of Ewing's sarcoma: preliminary results. A protocol of the French Pediatric Oncology Society (SFOP). Cancer Chemother Pharmacol. 1989;24 Suppl 1:S45-7. doi: 10.1007/BF00253240.

  PMID: 2667789 BACKGROUND

• Burdach S, Jurgens H, Peters C, Nurnberger W, Mauz-Korholz C, Korholz D, Paulussen M, Pape H, Dilloo D, Koscielniak E, et al. Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma. J Clin Oncol. 1993 Aug;11(8):1482-8. doi: 10.1200/JCO.1993.11.8.1482.

  PMID: 8101562 BACKGROUND

• Baird K, Fry TJ, Steinberg SM, Bishop MR, Fowler DH, Delbrook CP, Humphrey JL, Rager A, Richards K, Wayne AS, Mackall CL. Reduced-intensity allogeneic stem cell transplantation in children and young adults with ultrahigh-risk pediatric sarcomas. Biol Blood Marrow Transplant. 2012 May;18(5):698-707. doi: 10.1016/j.bbmt.2011.08.020. Epub 2011 Sep 5.

  PMID: 21896345 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Sarcoma; Sarcoma, Ewing; Rhabdomyosarcoma; Desmoplastic Small Round Cell Tumor

Interventions

Fluorodeoxyglucose F18; Cyclophosphamide; Cyclosporine; Doxorubicin; Etoposide; fludarabine phosphate; Melphalan; Prednisone; Sirolimus; Tacrolimus; Vincristine; Peripheral Blood Stem Cell Transplantation; Filgrastim

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Myosarcoma; Neoplasms, Muscle Tissue

Intervention Hierarchy (Ancestors)

Deoxyglucose; Deoxy Sugars; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Aminoglycosides; Glycosides; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Macrolides; Lactones; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Terry Fry
• Organization: National Cancer Institute, National Institutes of Health

fryt@mail.nih.gov

301-402-0215

Study Officials

• Terry Fry, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 15, 2002
• First Posted: August 16, 2002
• Study Start: September 19, 2002
• Primary Completion: May 1, 2009
• Study Completion: December 14, 2011
• Last Updated: May 31, 2017
• Results First Posted: September 13, 2013

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)