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

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

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.

Study Overview

• Status: Completed
• Conditions: Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: cyclophosphamide; Drug: etoposide; Drug: cisplatin; Procedure: peripheral blood stem cell transplantation; Drug: paclitaxel; Biological: filgrastim; Drug: ifosfamide; Drug: mesna

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Sequential high dose chemotherapy	Drug: carboplatin; Drug: cyclophosphamide; Drug: etoposide; Drug: cisplatin; Procedure: peripheral blood stem cell transplantation; Drug: paclitaxel; Biological: filgrastim; Drug: ifosfamide; Drug: mesna

What is the study measuring?

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

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: December 1, 1994
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): August 26, 2015
• Last Update Submitted That Met QC Criteria: August 24, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; recurrent breast cancer; stage IIIB breast cancer; stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer; recurrent pancreatic cancer; stage III ovarian epithelial cancer; stage IV ovarian epithelial cancer; recurrent ovarian epithelial cancer; stage II breast cancer; recurrent melanoma; stage IV melanoma; stage IV pancreatic cancer; stage IV gastric cancer; recurrent gastric cancer; stage IV anal cancer; recurrent anal cancer; advanced adult primary liver cancer; recurrent adult primary liver cancer; recurrent gallbladder cancer; recurrent extrahepatic bile duct cancer; recurrent small intestine cancer; localized osteosarcoma; stage III melanoma; stage IV adult soft tissue sarcoma; recurrent adult soft tissue sarcoma; recurrent esophageal cancer; stage II melanoma; stage IV esophageal cancer; metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; metastatic osteosarcoma; recurrent osteosarcoma; stage III adult soft tissue sarcoma; recurrent Wilms tumor and other childhood kidney tumors
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Carboplatin; Etoposide; Paclitaxel; Ifosfamide
• Other Study ID Numbers: 94098; P30CA033572 (U.S. NIH Grant/Contract); CHNMC-IRB-94098; NCI-V96-1042; CDR0000065102 (Registry Identifier: NCI PDQ)