High-Dose Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Advanced Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy plus peripheral stem cell transplantation in treating patients who have advanced cancer.

Detailed Description
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OBJECTIVES: Evaluate the feasibility of administering 2 courses of high dose chemotherapy consisting of etoposide, cisplatin, and cyclophosphamide followed by ifosfamide, carboplatin, and paclitaxel (IC-T), each administered with filgrastim (G-CSF) and autologous stem cell support, to patients with advanced carcinomas. Describe the toxicity of these high dose chemotherapy regimens. Define the maximum tolerated dose of paclitaxel deliverable in this high dose regimen. Describe the pharmacokinetics of escalating doses of paclitaxel given as a 24-hour continuous infusion. Determine the disposition of carboplatin administered in the IC-T regimen. OUTLINE: At least 4 weeks prior to chemotherapy, patients undergo stem cell collection following filgrastim (G-CSF) mobilization. Sufficient stem cells to support 2 courses of chemotherapy are required. Autologous bone marrow is collected as an adjuvant if stem cell harvest is inadequate. Patients then receive high dose cisplatin, etoposide, and cyclophosphamide over 10 days, followed the next day by infusion of one fourth of the allotted stem cells, with the remaining allotment infused 2 days later. G-CSF is given for granulocyte support. Beginning no sooner than 14 weeks from the start of the first course of chemotherapy, stable and responding patients receive high dose paclitaxel, carboplatin, and ifosfamide over 5 days, followed 2 days later with one-fourth of the allotted stem cells, with the remaining allotment infused the following day. G-CSF is given for granulocyte support. Groups of 3-6 patients are treated with escalating doses of paclitaxel until the maximum tolerated dose for this regimen is determined. Patients are followed monthly for 1 year, every 3 months for 1 year, then as needed at the physician's discretion for at least 5 years. PROJECTED ACCRUAL: Three to six patients will be entered at each dose of paclitaxel studied.

Official Title
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PHASE I PILOT STUDY OF SEQUENTIAL HIGH DOSE CYCLES OF CISPLATIN, CYCLOPHOSPHAMIDE, ETOPOSIDE AND IFOSFAMIDE, CARBOPLATIN AND TAXOL WITH AUTOLOGOUS STEM CELL SUPPORT

Conditions
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Cancer

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Drug: ifosfamide
* Drug: mesna
* Drug: paclitaxel
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed advanced carcinomas of the following types: Breast carcinoma that is ineligible for or patient has refused participation in a higher priority protocol in the following categories: Stage II disease with at least 10 involved lymph nodes and no evidence of disease (NED) following surgery Stage III disease rendered surgically NED with or without radiotherapy Stage IV disease following partial response (PR) or complete response (CR) to surgery, chemotherapy, or radiotherapy Prior high dose chemotherapy allowed at discretion of investigator No chemoresistant disease rendered surgically NED Locoregionally recurrent disease within 2 years of breast conservation with or without chemotherapy Stage III/IV ovarian cancer PR/CR following debulking surgery and/or chemotherapy Ineligible for or refused participation in higher priority protocols Primary soft tissue sarcoma with high-grade disease greater than 10 cm or that is metastatic Rendered surgically NED or achieved PR/CR on any chemotherapeutic or immunotherapeutic regimen Ineligible for or refused participation in higher priority protocols Malignant melanoma in the following categories: Ulcerative primary tumor with any number of completely resected metastatic lymph nodes Stage II disease with more than 4 involved nodes rendered NED Stage III disease rendered surgically NED or achieved PR/CR on any chemotherapeutic or immunotherapeutic regimen Osteosarcoma that is ineligible for or refused participation in higher priority protocols Resected primary with less than 50% tumor necrosis on pathologic review Metastatic disease rendered surgically NED or PR/CR on any chemotherapeutic, radiotherapeutic, or immunotherapeutic regimen The following diseases rendered surgically NED or that achieved PR/CR on any chemotherapeutic, radiotherapeutic, or immunotherapeutic regimen also eligible: Small cell bone carcinoma Metastatic Ewing's sarcoma Metastatic gastrointestinal malignancy Recurrent Wilms' tumor No CNS metastases No current histologically confirmed bone marrow metastases Prior bone metastases with resolution at time of entry permitted PATIENT CHARACTERISTICS: Age: Physiologic 18 to 55 Performance status: Karnofsky 80%-100% Hematopoietic: Absolute neutrophil count greater than 1,500/mm3 Platelet count greater than 120,000/mm3 Hemoglobin greater than 10 g/dL Hepatic: Bilirubin less than 1.5 mg/dL AST/ALT less than 3 times normal Renal: Creatinine less than 1.4 mg/dL Creatinine clearance at least 70 mL/min No history of hemorrhagic cystitis Cardiovascular: Ejection fraction at least 55% by MUGA No significant cardiac disease Pulmonary: FEV1 greater than 2 L pO2 (room air) greater than 70 mm Hg pCO2 (room air) less than 42 mm Hg DLCO greater than 60% of predicted Other: No potentially disabling psychosocial history No organic or functional CNS dysfunction or other medical problem that would present party at undue risk HIV negative Hepatitis B surface antigen negative No hearing loss greater than 40 decibels No contraindication to the following procedures: Collection by apheresis of up to 16 x 10 to the 8th mononuclear cells mobilized by G-CSF Collection of autologous bone marrow, if needed No second malignancy except: Nonmelanomatous skin cancer Carcinoma in situ of the cervix Not pregnant or nursing Adequate contraception required of fertile patients PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics At least 4 weeks since prior immunotherapy Chemotherapy: See Disease Characteristics No more than 3 prior chemotherapy regimens (excluding adjuvant therapy) No more than 200 mg per square meter of prior cisplatin No more than 800 mg per square meter of prior carboplatin No prior exposure to greater than 1,000 mg per square meter of 24-hour paclitaxel equivalents (using a 1:1.3 ratio between paclitaxel doses given by 24-hour infusion and by 3-hour infusion) At least 4 weeks since prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy to more than 20% of bone marrow At least 4 weeks since prior radiotherapy Surgery: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential high dose chemotherapy<br> | Biological: filgrastim<br> <br> Drug: carboplatin<br> <br> Drug: cisplatin<br> <br> Drug: cyclophosphamide<br> <br> Drug: etoposide<br> <br> Drug: ifosfamide<br> <br> Drug: mesna<br> <br> Drug: paclitaxel<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of two cycles of high dose chemotherapy with stem cell reinfusion |  | 30 days from start of course II of treatment | 
| Toxicity of two cycles of high dose chemothearpy and stem cell reinfusion | Toxicity graded according to the NCI Common Toxicity Criteria and amended for subjects undergoing transplantation | 30 days from start of course II of treatment | 
| Maximum tolerated dose of two cycles of high dose chemothearpy and stem cell reinfusion |  | 30 days from start of course II of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent anal cancer, stage IV colon cancer, stage II breast cancer, stage IV breast cancer, stage IIIA breast cancer, recurrent breast cancer, stage IV gastric cancer, recurrent gastric cancer, localized osteosarcoma, metastatic osteosarcoma, stage IIIB breast cancer, recurrent pancreatic cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, stage IV anal cancer, stage IV esophageal cancer, recurrent esophageal cancer, stage III adult soft tissue sarcoma, recurrent adult soft tissue sarcoma, stage III ovarian epithelial cancer, stage IV ovarian epithelial cancer, recurrent ovarian epithelial cancer, recurrent Wilms tumor and other childhood kidney tumors, advanced adult primary liver cancer, recurrent adult primary liver cancer, recurrent osteosarcoma, recurrent gallbladder cancer, recurrent extrahepatic bile duct cancer, recurrent small intestine cancer, stage II melanoma, stage III melanoma, stage IV melanoma, recurrent melanoma, metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, stage IV adult soft tissue sarcoma, stage IV pancreatic cancer