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

Phase 2

Completed

Conditions: Sarcoma

Interventions: Drug: F-18 Fluorodeoxyglucose
Biological: therapeutic allogeneic lymphocytes
Procedure: Peripheral Blood Stem Cell donation
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

Registration Number: NCT00043979

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: Background:

* Treatment of pediatric sarcomas has enjoyed progress in the past 25 years for patients with localized, chemosensitive disease and prognostic factors are now available to identify subsets of patients who have very dismal prognoses; patients with primary metastatic disease, especially those with bone and bone marrow metastases.

* Patients with primary chemoresistant disease and early recurrence also have very poor prognoses and lack suitable treatment options. For these patients, it is critical that alternative approaches to cytotoxic chemotherapy be identified.

* Basic laboratory studies have shown that Ewing's sarcoma is susceptible to immune mediated mechanisms of cytolysis in vitro. Interestingly, for Ewing's sarcoma this appears to be true for both chemosensitive and chemoresistant cell lines.

* Recent progress in the field of bone marrow transplantation has identified approaches that can reproducibly induce allogeneic peripheral blood stem cell engraftment in adults with hematologic malignancies. In some cases, this same approach has shown beneficial effects for patients with solid tumors as a result of the development of allogeneic, immune-mediated graft versus tumor effects.

Objectives:

* To determine if the transplantation of human leukocyte antigen (HLA) matched, peripheral blood stem cells can result in full donor engraftment (greater than 95 percent by day 100) in patients with high risk-pediatric sarcomas.

* To identify and characterize the toxicities of HLA-matched peripheral blood stem cell transplant (PBSCT) in patients with high-risk pediatric sarcomas. In particular we will identify the incidence of graft versus host disease (GVHD) and the pace of immune reconstitution in this population.

* To determine if allogeneic graft-versus-tumor responses following allogeneic PBSCT can induce clinically significant anti-tumor effects as measured by radiographic evidence of antitumor responses following PBSCT in patients with measurable disease and improved clinical outcome compared to historical controls in this patient population with a universally poor outcome.

Eligibility:

* Patients, age of greater than 4 years at enrollment to less than 30 years at diagnosis and age less than 35 at enrollment, with ultra-high risk Ewing's sarcoma family of tumors, desmoplastic small round cell tumor or alveolar rhabdomyosarcoma.

* Patients must have completed standard front-line therapy and salvage therapy.

* Patient must have the availability of a 5 or 6 antigen HLA-matched first-degree relative donor or a genotypically identical twin.

* Patients must have adequate cardiac, pulmonary, renal, liver, and marrow function.

Design:

-Donor will be prepared for peripheral blood stem cell harvest with Filgrastim mobilization, 10 microg/kg per day subcutaneous (SQ) for 5-7 days until they have stem cell collected by apheresis. The stem cells will then be cryopreserved.

Patients will receive 1 to 3 21 day cycles of Fludarabine-EPOCH induction chemotherapy. The preparative regimen will consist of cyclophosphamide, fludarabine and melphalan followed by stem cell infusion. GVHD prophylaxis will consist of sirolimus and tacrolimus.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 2 - Recipients	Filgrastim	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.
Arm 2 - Recipients	therapeutic allogeneic lymphocytes	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.
Arm 1- Sibling Donors	Peripheral Blood Stem Cell donation	Donors (n = 30) were matched first degree relatives who were eligible to donate peripheral blood stem cells.
Arm 2 - Recipients	F-18 Fluorodeoxyglucose	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.
Arm 2 - Recipients	melphalan	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.
Arm 2 - Recipients	vincristine sulfate	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.
Arm 2 - Recipients	peripheral blood stem cell transplantation	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.
Arm 1- Sibling Donors	Filgrastim	Donors (n = 30) were matched first degree relatives who were eligible to donate peripheral blood stem cells.
Arm 2 - Recipients	cyclophosphamide	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.
Arm 2 - Recipients	cyclosporine	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.
Arm 2 - Recipients	fludarabine phosphate	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.
Arm 2 - Recipients	doxorubicin hydrochloride	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.
Arm 2 - Recipients	etoposide	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.
Arm 2 - Recipients	prednisone	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.
Arm 2 - Recipients	sirolimus	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.
Arm 2 - Recipients	tacrolimus	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Engraftment	100 days	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.
Toxicity	16.5 months	Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Secondary Outcome Measures

Name	Time	Method
Median Time to Reach Absolute Neutrophil Count of 500/mm(3)	up to 12 days	Days for participants to achieve a neutrophil count of 500/mm(3).
Early Post Transplantation Relapse	up to 300 days	Participants who experienced recurrence or progression of disease following transplant.
Cluster of Differentiation 4 (CD4) Reconstitution	Day +28-42	The median CD4 count with a range of 85-1565 (absolute count) was used to determine recovery and were considered recovered if in this range. The CD4 count was established by flow cytometry testing.
Median Survival From Date of Progression	up to 77 months	Median survival from date of progression is based on the time from on-study date until progression or last follow-up.
Number of Participants With Acute and Chronic GVHD	up to 5 years or death	Acute GVHD as by Modified Glucksberg Criteria occurring before day 100. Chronic GVHD as per Seattle criteria occurring after day 100.
Two Year Survival Rate for Patients Undergoing Allo-Hematopoietic Stem Cell Transplant	2 years	Participants who are alive at two years following Allo-Hematopoietic Stem Cell Transplant.
Median Progression Free Survival	up to 77 months	Progression free survival was based on the time from on-study date until progression or last follow-up.
Number of Participants to Complete Conversion to >95% Donor Chimerism	up to 30 days	Participants who tolerated the transplantation regimen and accepted \>95% of the donors blood, marrow, and/or tissue.
Median Time to Reach a Platelet Count of 50,000/mm(3)	up to 43 days	Days for participants to achieve a platelet count of 50,000/mm(3).
Best Response Post-Hematopoietic Stem Cell Transplant EOCH (Etoposide, Vincristine, Cyclophosphamide, and Doxorubicin)	up to 10 cycles of therapy or 280 days	Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). RECIST criteria offer a simplified, conservative, extraction of imaging data for wide application in clinical trials. They presume that linear measures are an adequate substitute for 2-D (dimensional) methods and registers four response categories: Complete response (CR) is disappearance of all target lesions. Partial response (PR) is 30% increase in the sum of the longest diameter of target lesions. Progressive disease (PD) is 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) is small changes that do not meet above criteria. For the purposes of this study very good partial response ((VGPR) is \>75% reduction in disease) was also employed.