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Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Sarcoma

High-Dose Doxorubicin and Ifosfamide Followed by Melphalan and Cisplatin for Patients With High-Risk and Recurrent Sarcoma

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00002601
Enrollment
13
Registered
2004-03-11
Start date
1994-09-30
Completion date
2014-09-30
Last updated
2017-03-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sarcoma

Keywords

metastatic osteosarcoma, recurrent childhood rhabdomyosarcoma, recurrent adult soft tissue sarcoma, recurrent osteosarcoma, adult rhabdomyosarcoma, metastatic childhood soft tissue sarcoma, recurrent childhood soft tissue sarcoma, previously treated childhood rhabdomyosarcoma, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, stage IV adult soft tissue sarcoma

Brief summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of high-dose combination chemotherapy and peripheral stem cell transplantation in treating patients who have advanced or recurrent sarcoma.

Detailed description

OBJECTIVES: I. Determine the feasibility of sequential high-dose chemotherapy with ifosfamide and doxorubicin followed by melphalan and cisplatin, each followed by autologous peripheral blood stem cell support, in patients with high-risk or advanced sarcomas. II. Determine the toxic effects of this regimen in these patients. III. Determine response rate and disease-free and overall survival in these patients treated with this regimen. OUTLINE: Beginning at least 4 weeks prior to the start of chemotherapy, patients receive filgrastim (G-CSF) subcutaneously daily until the completion of peripheral blood stem cell (PBSC) harvesting. Beginning 5 days after the start of G-CSF, PBSCs are collected over several days. Patients who do not mobilize sufficient cells undergo bone marrow harvest. Regimen A: Patients receive high-dose ifosfamide IV and doxorubicin IV continuously over 96 hours on days -8 to -4. 12.5% of PBSCs or bone marrow are reinfused on day -2 and 37.5% are reinfused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover. Regimen B: Beginning at least 4 weeks after day 1 of Regimen A, patients receive high-dose melphalan IV followed immediately by cisplatin IV on days -11 and -4. Patients receive G-CSF IV on days -10 to -6. 12.5% of PBSCs or bone marrow are reinfused on day -3 and the remaining 37.5% are reinfused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover. Patients are followed monthly for 1 year, every 3 months for 1 year, and then as needed for 3 years. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 3 years.

Interventions

BIOLOGICALfilgrastim

5 ug/kg daily following stem cell reinfusion

DRUGcisplatin

Course 2 - 100 mg/m2 at an infusion rate of 25 mg/hr

DRUGdoxorubicin hydrochloride

Course 1 - 150 mg/m2 by continuous intravenous infusion for 96 hours.

DRUGifosfamide

Course 1 - 14 gm/M2 by continuous intravenous infusion for 96 hours.

DRUGmelphalan

Course 2 - 75 mg/m2 infused at a rate of 5 mg/minute

PROCEDUREperipheral blood stem cell transplantation

Administered on Day 0 following high-dose chemotherapy in both courses 1 and 2

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
City of Hope Medical Center
Lead SponsorOTHER

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
10 Years to 55 Years
Healthy volunteers
No

Inclusion criteria

DISEASE CHARACTERISTICS: Histologically confirmed sarcomas in the following categories: Soft tissue sarcoma (STS) High-grade STS of the extremities Primary extending to fascia or locally recurrent At least 10 cm in greatest dimension or multifocal on surgical pathology Primary site controlled by surgery and/or radiotherapy High-grade truncal or head and neck sarcoma At least 10 cm in greatest dimension or any size with no surgical options for clear margins Primary site controlled by surgery and/or radiotherapy Locally recurrent disease in CR or PR after surgery, chemotherapy, or radiotherapy Metastatic STS in CR or PR after surgery, chemotherapy, or radiotherapy Osteosarcoma (OS) Extremity OS after neoadjuvant chemotherapy and surgical resection provided: Less than 50% necrosis in the surgical specimen LDH or alkaline phosphatase greater than 2 times normal at presentation Axial OS in CR or PR after chemotherapy and/or surgery Primary or recurrent metastatic OS in CR or PR after chemotherapy, surgery, and/or radiotherapy Ewing's sarcoma or primitive neuroectodermal tumor Primary site in CR or PR after chemotherapy, radiotherapy, or surgery Rib, pelvic, or axial skeleton primary Bulky tumor (at least 10 cm in greatest diameter) Primary or recurrent metastatic disease in CR or PR after surgery, chemotherapy, or radiotherapy Rhabdomyosarcoma Gross residual disease after primary treatment with surgery, chemotherapy, and radiotherapy Primary group IV or recurrent metastatic disease in CR or PR after chemotherapy and radiotherapy with or without surgery No brain metastasis No histologically confirmed bone marrow metastasis Prior metastases allowed with clearing of bone marrow at entry No contraindication to collection of mobilized stem cells or, if needed, autologous bone marrow PATIENT CHARACTERISTICS: Age: 10 to 55 Performance status: Karnofsky 80-100% Hematopoietic: Absolute neutrophil count greater than 2,000/mm3 Platelet count greater than 150,000/mm3 Hemoglobin greater than 10 g/dL Hepatic: See Disease Characteristics Bilirubin less than 1.5 mg/dL AST and ALT less than 3 times normal Hepatitis B surface antigen negative Negative hepatitis C antigen test required in patients with hepatitis C antibody Renal: Creatinine less than 1.4 mg/dL Creatinine clearance greater than 75 mL/min Cardiovascular: LVEF at least 55% by MUGA or echocardiogram No history of significant cardiac disease Pulmonary: FEV1 greater than 2 liters PaO2 greater than 70 mm Hg on room air PaCO2 less than 42 mm Hg on room air DLCO greater than 60% predicted Other: No hearing loss of greater than 40 decibels HIV negative No organic or psychiatric CNS dysfunction that would preclude study No other medical or psychosocial problems that would place patient at unacceptable risk No history of other malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix Not pregnant Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: More than 2 weeks since treatment to control primary or recurrent tumor Biologic therapy: Not specified Chemotherapy: See Disease Characteristics No more than 2 prior chemotherapy regimens (including adjuvant therapy) Prior cumulative cisplatin dose less than 400 mg/m2 Prior cumulative doxorubicin dose less than 240 mg/m2 Endocrine therapy: Not specified Radiotherapy: See Disease Characteristics No prior radiotherapy to more than 20% of the bone marrow-containing axial skeleton No prior radiotherapy to the left chest wall Surgery: See Disease Characteristics

Design outcomes

Primary

MeasureTime frameDescription
Number of Participants With Grade 3 Bilirubin2 years after completion of treatmentCriteria for early termination of this feasibility study: \> 2 patients experience grade 4 or 5 hematologic toxicity or more that 3 patients experience grade 3 hematologic toxicity; \> 2 patients experience grade 3 hepatic or gastrointestinal toxicity or \> 3 patients are unable to receive the second cycle of treatment; \> 2 patients experience grade 5 toxicity related to treatment regimen.
Toxicities Counts2 months after completion of second cycle of treatment.Number of patients with grade 3 and 4 toxicities observed during cycles 1 & 2 using the Common Toxicity Criteria Version for Chemotherapy.

Secondary

MeasureTime frameDescription
5-year Progression-free SurvivalUntil disease progression, up to 5 YearsEstimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 25% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.
5-year Overall SurvivalUntil death from any cause, up to 5 yearsEstimated using the product-limit method of Kaplan and Meier.

Countries

United States

Participant flow

Participants by arm

ArmCount
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT
Cycle 1 Day -8 through Day -4 (96h) Doxorubicin 150 mg/m2 (CI) + Ifosfamide 14 g/m2 mixed with mesna (CI) Day -3 Mesna 3.5 g/m2 over 24 h Day -2 12.5% of stem cell reinfused. Cycle2 Day -11 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -10 thru Day -6 G-CSF 5ug/kg Day -4 Melphalan 75 mg/m2 + Cisplatin 100 mg/m2 Day -3 12.5% if stem cell reinfused Day 0 37.5% of stem cell reinfused
13
Total13

Baseline characteristics

CharacteristicDoxorubicin/Ifosfamide + Melphalan/CDDP + PSCT
Age, Continuous31 years
Region of Enrollment
United States
13 participants
Sex: Female, Male
Female
3 Participants
Sex: Female, Male
Male
10 Participants

Adverse events

Event typeEG000
affected / at risk
deaths
Total, all-cause mortality
— / —
other
Total, other adverse events
13 / 13
serious
Total, serious adverse events
3 / 13

Outcome results

Primary

Number of Participants With Grade 3 Bilirubin

Criteria for early termination of this feasibility study: \> 2 patients experience grade 4 or 5 hematologic toxicity or more that 3 patients experience grade 3 hematologic toxicity; \> 2 patients experience grade 3 hepatic or gastrointestinal toxicity or \> 3 patients are unable to receive the second cycle of treatment; \> 2 patients experience grade 5 toxicity related to treatment regimen.

Time frame: 2 years after completion of treatment

ArmMeasureValue (NUMBER)
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTNumber of Participants With Grade 3 Bilirubin3 participants with Grade 3 Bilirubin
Primary

Toxicities Counts

Number of patients with grade 3 and 4 toxicities observed during cycles 1 & 2 using the Common Toxicity Criteria Version for Chemotherapy.

Time frame: 2 months after completion of second cycle of treatment.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsElevated PTT1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsLeukopenia13 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsNeutropenia13 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsFebrile neutropenia13 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsThrombocytopenia13 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsMucositis13 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsBacteremia/sepsis2 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsHyperglycemia5 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsPulmonary function impairment (FEV1)1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsPulmonary infiltrates0 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsDiarrhea1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsArrhythmia1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsHematuria1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsMood1 Participants
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCTToxicities CountsAnemia8 Participants
Cycle 2Toxicities CountsDiarrhea0 Participants
Cycle 2Toxicities CountsElevated PTT0 Participants
Cycle 2Toxicities CountsAnemia3 Participants
Cycle 2Toxicities CountsHyperglycemia1 Participants
Cycle 2Toxicities CountsLeukopenia11 Participants
Cycle 2Toxicities CountsHematuria0 Participants
Cycle 2Toxicities CountsNeutropenia11 Participants
Cycle 2Toxicities CountsPulmonary function impairment (FEV1)0 Participants
Cycle 2Toxicities CountsFebrile neutropenia9 Participants
Cycle 2Toxicities CountsArrhythmia1 Participants
Cycle 2Toxicities CountsThrombocytopenia11 Participants
Cycle 2Toxicities CountsPulmonary infiltrates2 Participants
Cycle 2Toxicities CountsMucositis1 Participants
Cycle 2Toxicities CountsMood1 Participants
Cycle 2Toxicities CountsBacteremia/sepsis4 Participants
Secondary

5-year Overall Survival

Estimated using the product-limit method of Kaplan and Meier.

Time frame: Until death from any cause, up to 5 years

ArmMeasureValue (NUMBER)
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT5-year Overall Survival31 percentage of participants
Secondary

5-year Progression-free Survival

Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 25% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.

Time frame: Until disease progression, up to 5 Years

ArmMeasureValue (NUMBER)
Doxorubicin/Ifosfamide + Melphalan/CDDP + PSCT5-year Progression-free Survival23 percentage of participants

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026