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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Biological: filgrastim; Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: ifosfamide; Drug: melphalan; Procedure: peripheral blood stem cell transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • Cancer Center and Beckman Research Institute, City of Hope

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Biological: filgrastim; 5 ug/kg daily following stem cell reinfusion; Drug: cisplatin; Course 2 - 100 mg/m2 at an infusion rate of 25 mg/hr; Drug: doxorubicin hydrochloride; Course 1 - 150 mg/m2 by continuous intravenous infusion for 96 hours.; Drug: ifosfamide; Course 1 - 14 gm/M2 by continuous intravenous infusion for 96 hours.; Drug: melphalan; Course 2 - 75 mg/m2 infused at a rate of 5 mg/minute; Procedure: peripheral blood stem cell transplantation; Administered on Day 0 following high-dose chemotherapy in both courses 1 and 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 years after completion of treatment
Toxicities Counts	Number of patients with grade 3 and 4 toxicities observed during cycles 1 & 2 using the Common Toxicity Criteria Version for Chemotherapy.	2 months after completion of second cycle of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Until disease progression, up to 5 Years
5-year Overall Survival	Estimated using the product-limit method of Kaplan and Meier.	Until death from any cause, up to 5 years

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: George Somlo, MD, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: September 1, 1994
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: March 10, 2004
• First Posted (Estimate): March 11, 2004

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: January 18, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: previously treated childhood rhabdomyosarcoma; recurrent childhood rhabdomyosarcoma; stage IV adult soft tissue sarcoma; recurrent adult soft tissue sarcoma; adult rhabdomyosarcoma; metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; metastatic osteosarcoma; recurrent osteosarcoma; metastatic childhood soft tissue sarcoma; recurrent childhood soft tissue sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Ifosfamide; Melphalan; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: 94072; P30CA033572 (U.S. NIH Grant/Contract); CHNMC-IRB-94072 (Registry Identifier: NCI PDQ); NCI-V94-0545; CDR0000063845 (Registry Identifier: NCI PDQ)